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Journal of Drug Delivery and Therapeutics

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Open Access Full Text Article                                                              Review Article

Receptor Tyrosine Kinase (RTKs) Mediated Potent Bioactive Ligand Targeted to Autoimmune Arthritis

Nikita Patel ¹ , Trilochan Satapathy *, Poonam Sahu , Pratibha Dhiwar , Kamaksha Tiwari , Laxmi Sahu 

Columbia Institute of Pharmacy, Village Tekari, Near Vidhansabha, Raipur-493111, C.G., India.

Graphical abstract

 

 

1. Introduction:

A class of inflammatory joint illnesses known as autoimmune arthritis occurs when the body's own tissues, especially the joints, are mistakenly attacked by the immune system ¹. Chronic inflammation, discomfort, and joint degeneration are the results of an immunological reaction ². Among the different kinds of autoimmune arthritis, the rheumatoid arthritis (RA) is the most prevalent. The World Health Organization (WHO) estimates that up to 355 million people worldwide suffer with arthritis ³. Millions of people are impacted globally, caused by a variety of elements, such as illness, injury, heredity, and the immune system. The cause depends on the type of arthritis like Osteoarthritis (OA), Rheumatoid Arthritis (RA), Psoriatic Arthritis, Gout, and Juvenile Idiopathic Arthritis (JIA) ⁴. This condition arises due to wear and tear (degenerative changes), infections, genetic factors, metabolic disorders, lifestyle and environmental Factors. According to statistics, the prevalence of arthritis in American countries range is 21.2% of U.S. adults (53.2 million people), while in European countries ranges from 0.29% to 0.57% ⁵.Conventional treatments for autoimmune arthritis, including corticosteroids, disease-modifying anti-rheumatic medications (DMARDs), and non-steroidal anti-inflammatory drugs (NSAIDs), can be useful in controlling symptoms and delaying the course of the condition, but they also have a number of drawbacks and possible adverse effects ⁶. Long-term usage of NSAIDs (such as naproxen and ibuprofen) can have varying effects on different organs ⁷. These can aggravate the lining of the stomach resulting in gastric ulcers and bleeding, kidney strain that may cause kidney damage or diminished kidney function, increased risk of heart attack or stroke especially in those with pre-existing heart conditions as well as affect liver function in certain individuals resulting in elevated liver enzymes and possibly causing liver damage⁸. Similarly, corticosteroids enhance fluid retention, resulting in considerable weight gain and swelling. Their use for an extended period can weaken bones, raising the risk of fractures, and weaken the immune system, leaving people more vulnerable to infections⁹. These restrictions frequently lead to the pursuit of more specialized or alternative treatments. Bioactive substances found in a variety of plants have been found to interact with Receptor Tyrosine Kinases (RTKs), preventing their over activation and lowering the inflammation and accelerating the healing process ¹⁰. Substances like resveratrol (found in grapes), curcumin (found in turmeric), and epigallocatechin gallate (EGCG) (found in green tea) have demonstrated encouraging results in inhibiting signaling pathways linked to RTK ¹¹. These substances can lower oxidative stress, inhibit pro-inflammatory cytokines, and shield cartilage from deterioration-all of these are essential for regulating the course of arthritis. Herbal bioactive that target RTKs may provide a safer, more natural substitute or supplement of traditional medication therapy ¹². 

 

 

Figure 1: Diagrammatic representation of etiology of arthritis.

 

 

 

 

 

Figure 1: Overview of Inflammo-modulation by potent bioactives (Polyphenol) via T-cell and B-cells mediated signalling.

 

Demographic profile:

In this paper, we have tried to gather the age and prevalence basis data of rheumatoid arthritis (RA) and osteoarthritis (OA). Nowadays, Arthritis (RA and OA) has been a concerning disorder. We gather the data in India and worldwide based on surveys and reports. There are roughly 9.2 million people with RA in India, which represents 0.92% of the adult population. The disease primarily affects women, and it is more common in those between the ages of 20 and 40 ¹³. About 18 million people worldwide suffer from RA, with women making up around 70% of that afflicted. In 2019, rheumatoid arthritis affected 18 million persons globally ¹⁴. Women make up over 70% of those with rheumatoid arthritis, and 55% of those over 55 have the disease. Rehabilitation could be beneficial for 13 million individuals with moderate to severe rheumatoid arthritis ¹⁵.The data has been graphically represented below:

Figure 3: Graphical representation of prevalence of RA and OA in India.

 

Figure 4: Graphical representation of prevalence of RA and OA by age group.

Table 1: Comparison between RA and OA.

Feature	Rheumatoid Arthritis (RA)	Osteoarthritis (OA)	Ref
Prevalence	0.92% in India, 1% globally	62.35 million in India, 595 million globally	16
Gender distribution	Predominantly women, 70% of global cases	Predominantly women, especially over 55	17
Age group affected	Mostly 20-40 years in India, older adults globally	Primarily older adults, more common post-55	18
Common joints affected	Hands, wrists, knees	Knees, hips, hands
Risk factors	Genetics, smoking, autoimmune triggers	Age, obesity, joint injuries
Impact	Significant disability, especially in younger adults	Disability due to joint degeneration in elderly

 

 

2. Pathophysiology of arthritis:

The pathophysiology of arthritis varies depending on the type but generally involves a combination of inflammation, cartilage degradation, and bone remodeling. Pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 are released when immune cells infiltrate the synovium due to an autoimmune reaction in inflammatory arthritis, such as rheumatoid arthritis ¹⁹. This encourages angiogenesis, pannus development, and synovial hyperplasia, all of which weaken bone and cartilage ²⁰.

2.1 Pathophysiology of Osteoarthritis: Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive breakdown of articular cartilage, subchondral bone remodeling, synovial inflammation, and the formation of osteophytes (bone spurs) ²¹. Mechanical stress and metabolic alterations that result in chondrocyte dysfunction are the first signs of the disease ²². When these chondrocyte, which are in charge of preserving cartilage, become unbalanced, they produce too many matrix-degrading enzymes, such as matrix metalloproteinases (MMPs), which degrade collagen and proteoglycans and cause cartilage erosion ²³. The underlying subchondral bone experiences sclerosis and cyst development as cartilage degrades, which exacerbates joint pain and stiffness ²⁴. The pro-inflammatory cytokines include IL-1β, TNF-α, and IL-6 causes synovial inflammation, which starts cartilage degradation and increases pain by activating nerve endings ²⁵. 

2.2 Pathophysiology of Rheumatoid arthritis (RA): Inflammation of the synovial joints causes joint damage and possible deformity in rheumatoid arthritis (RA), a chronic inflammatory disease ²⁶. Environmental variables, dysregulated immune responses, and genetic predisposition all contribute to the Pathophysiology of RA ²⁷. By altering immune system function, genetic risk factors specifically, changes in the HLA-DRB1 gene predispose people to RA ²⁸. In people who are genetically predisposed, environmental triggers like smoking and infections can cause the condition to start by causing the synthesis of citrullinated proteins, which the immune system mistakenly interprets ²⁹. This sets off an autoimmune reaction in which the body's immune system produces rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), which result in the creation of immune complexes that accumulate in the synovium ³⁰. These complexes trigger the release of pro-inflammatory cytokines such TNF-α, IL-1, and IL-6 by activating T-cells, B-cells, and macrophages ³¹. Chronic inflammation is fueled by the cytokines, which thicken and inflame the synovium, resulting in the formation of a proliferative tissue known as pannus ³². Bone resorption and cartilage deterioration result from the pannus' invasion of the bone and cartilage. Additionally, the generation of matrix metalloproteinases, which degrade joint structures, is stimulated by activated immune cells ³³. Deformities, loss of function, and joint degradation are the outcomes. Systemic inflammation can also result in extra-articular symptoms such vasculitis, cardiovascular illness, and exhaustion ³⁴. Untreated or insufficiently managed RA can cause gradual joint deterioration and disability over time. The Pathophysiology of the disease is mostly based on the interaction of autoimmunity, inflammation, and tissue damage ³⁵. 

 

    

Figure 5: A diagrammatic representation of pathophysiology of Rheumatoid Arthritis (RA).

Table 2: Molecular Target in Rheumatoid Arthritis

S. No.	Molecular Targets	Role	Occurrence	Example of Targeting Drugs	Ref
1.	Cyclooxygenase pathway	Prostanoid biosynthesis, which produces biologically active compounds implicated in inflammation and other clinical problems	Cytosol and  tissue	Celecoxib, Piroxicam,  Naproxen, Valdecoxib	36
2.	Tumor Necrosis Factor-α	MMPs, adhesion molecules, endothelial cells, synovial fibroblasts, macrophages, and the release of additional cytokines and PGs are all activated.	Synovial fluid  and tissue	Infliximab, Etanercept,  Adalimumab, Golimumab,  Certolizumab pegol	37
3.	Interleukin-1	Strong MMP and eicosanoid inducer, NF-κB ligand receptor activator, and hyaline cartilage formation inhibitor.	Synovium	Anakinra	38
4.	Interleukin-6	Intercellular cell adhesion molecules 1 expression is upregulated, bone resorption occurs, and osteoclast activation occurs.	Serum and  synovial fluid	Tocilizumab, lactoferin	39
5.	Interleukin-8	Neutrophil Recruitment, Inflammatory Response, Angiogenesis, Cartilage and Bone Degradation	Synovium	ABX-IL8	40
6.	Interleukin-10	Reduce cytokine production and increase IL-1RA production along	Synovial  tissue	Pegilodecakin (AM0010), AMG 108, MDX-1100	41
7.	Matrix  Metalloproteinase	Involved in the deterioration of bone and cartilage	Joint  Synovium	Trocade (Ro 32-3555)	42
8.	Nuclear Factor-κB	Immune Response Regulation, Cell Survival and Apoptosis, Stress and Oxidative Response	Cytosol	Iguratimod	43
9.	Prostaglandin  (PG)	Inducing bone resorption	Osteocyte	Celecoxib, Piroxicam,  Naproxen, Valdecoxib	44
10.	B lymphocyte	Presentation of antigens and pro-inflammatory cytokine secretin	Bone marrow,  synovial  membrane	Rituximab	45

 

 

3. Conventional treatment options for Rheumatoid arthritis:

3.1 Disease-Modifying Anti-Rheumatic Drugs (DMARDs): DMARDs are effective in treating inflammatory joint illnesses, including RA; medications lessen the immunological reactions that cause pain and inflammation and slow the progression of joint deterioration ⁴⁶. If an entity has demonstrated its ability to prevent or postpone joint deterioration in RA on hand or foot radiographs, it is deemed disease-modifying. There are two main categories of DMARDs: conventional and biological DMARDs ⁴⁷. Biologic DMARDs are soluble receptors or monoclonal antibodies, while conventional DMARDs include medications like methotrexate and sulfasalazine ⁴⁸.

3.1.1 Conventional Synthetic DMARDs (csDMARDs): The conventional DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, cyclosporine, gold salts, D-penicillamine, and tetracycline ⁴⁹. It is traditional, non-biologic DMARDs that mainly suppress the immune system and have a slow half-life of several weeks. Methotrexate reduces the availability of folate ion, which is important for DNA synthesis and cellular growth, by inhibiting dihydrofolate reductase, also inhibits inflammatory immune cells that divide quickly and decreases the synthesis of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) ⁵⁰. Sulfasalazine inhibit the nuclear factor kappa-B (NF-kB), transcription factor, TNF-alpha expression by inducing caspase 8-induced apoptosis in macrophages, also inhibit the osteoclast development by inhibiting the expression of receptor activator of NF-kB ligand (RANKL) and osteoprotegerin; sulfasalazine inducethe conversion of adenine nucleotides to adenosine and its anti-inflammatory properties mediated by adenosine; inhibition of leukocyte accumulation through an adenosine-dependent mechanism; inhibition of B-cell function; and inhibition of the release of inflammatory chemokines interleukin-8, on the other side the Hydroxychloroquine interferes with antigen presentation and inhibits toll-like receptor signaling, reduce the activation of immune cells and decreasing cytokine production ^{51, 52, 53}.

3.1.2 Biologic DMARDs includes monoclonal antibodies, fusion proteins, therapeutic proteins, and deoxyribonucleic acid vaccines. They have incredibly complicated structures and are often 200–1000 times larger than a small molecule medicine ⁵⁴. Significant progress has been made in the treatment of RA since the introduction of these biological DMARDs. Etanercept suppresses the pro-inflammatory cytokine effects. Because of its shape, it can bind TNF 50–1000 times more strongly than naturally occurring TNF receptors ⁵⁵. 50 mg or 25 mg is the subcutaneous dosage that is given once or twice a week respectively; the half-life is three to six days. Patients were examined using either methotrexate combination therapy or etanercept monotherapy, and combination therapy produced better outcomes than monotherapy ⁵⁶. Etanercept can frequently be maintained at half the usual dosage in RA patients who have reached a stable low disease activity state while taking methotrexate plus it ⁵⁷. Infliximab is a chimeric (mouse Fv1, human IgG1) monoclonal antibody that forms stable, non-dissociating immune complexes by binding directly to soluble TNFα and membrane-binding with high affinity ⁵⁸. Since infliximab is a bivalent monoclonal antibody that permits the formation of multimeric complexes, it binds two soluble TNF trimers at the same time. Additionally, it increases recurrent signals and binds firmly to human cell TNF membranes. The dosage is determined by the patient's body weight and is typically between 3 and 10 mg/kg. It has a half-life of 7.7 to 9.5 days. Methotrexate is used in combination with infliximab. It increases the TNF blocker's effectiveness ⁵⁹.

3.2 Non-steroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs mainly inhibit the cyclooxygenase (COX) enzymes, COX-1 and COX-2, which is responsible for prostaglandin synthesis ⁶⁰. Lipid substances called prostaglandins mediate heat, discomfort, and inflammation. While COX-2 is inducible and mostly engaged in inflammatory reactions, COX-1 is constitutively produced and contributes to renal function, platelet aggregation, and the integrity of the gastrointestinal mucosa ⁶¹. NSAIDs decrease prostaglandin synthesis by inhibiting COX enzymes, which lowers inflammation, analgesia, and antipyresis ⁶². Another side, COX-1 inhibition may have negative consequences such as increased risk of bleeding, renal impairment, and stomach ulcers. In order to reduce gastrointestinal adverse effects while maintaining anti-inflammatory effectiveness ⁶³.

3.3 Corticosteroids have strong anti-inflammatory and immunosuppressive effects; they are frequently used as part of the traditional treatment for RA ⁶⁴. It lessens discomfort, control inflammation, and shield joints from harm. Corticosteroids suppress the immune system by inhibiting the pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) that play a key role in RA, also blocking the inflammatory pathways, reducing leukocyte activity and inhibiting the prostaglandins and leukotrienes; these molecules are involved in pain and inflammation; corticosteroids suppress the production of pro-inflammatory cytokines. Prednisone, methyl prednisolone, dexamethasone, hydrocortisone are the commonly used corticosteroids in RA ⁶⁵.

4. Prominent Herbal Bioactives Targeting RTKs in Arthritis:

According to many surveys and reports, we found that herbal medications are frequently chosen over conventional therapies because of their natural nature, perceived safety, and all-encompassing approach to healing. Many people think that herbal treatments are a kinder option for long-term use because they have fewer side effects than synthetic pharmaceuticals. Furthermore, herbal remedies have long been a crucial component of traditional medicinal systems, providing cultural importance and a sense of confidence. They are also more readily available and less expensive than a lot of pharmaceutical medications, which makes them a desirable option for anyone looking for economical medical care. Furthermore, herbal medicines frequently promote a balanced and preventive approach to health by concentrating on general well-being rather than only treating particular symptoms.The potential of herbal bioactive substances to modify tyrosine kinase pathways for the treatment of arthritis, especially rheumatoid arthritis (RA), has been investigated in recent studies. Through a variety of mechanisms, several natural substances have shown that encouraging anti-inflammatory and anti-arthritic effects.

 

 

Table 3: Classification and characteristics of the human RTKs and Human non receptor tyrosine kinase

Class	Family Name	Members	Molecular characteristics of the extracellular domains
Human Receptor Tyrosine Kinase: 66-71
I	EGFR	EGFR, ERBB2, ERBB3, ERBB4	2 cysteine-rich domains
II	Insulin R	INSR IGFR	2 chains α and β, with one cysteine-rich and 2 FNIII domains
III	PDGFR	PDGFRα, PDGFRβ, M-CSFR, KIT, FLT3L	5 Ig-like domains
IV	VEGFR	VEGFR1, VEGFR2, VEGFR3	7 Ig-like domains
V	FGFR	FGFR1, FGFR2, FGFR3, FGFR4	3 Ig-like domains, 1 acidic box
VI	CCK	CCK4	7 Ig-like domains
VII	NGFR	TRKA, TRKB, TRKC	2 Ig-like domains, rich leucin domains
VIII	HGFR	MET, RON	1 transmenbrane a chain linked with one extracellular b chain
IX	EPHR	EPHA1 to6, EPHB1to 6	1 Ig-like, 1 cysteine-rich and 2 FNIII-like domains
X	AXL	AXL, MER, TYRO3	2 Ig-line, 2 FNIII-like domains
XI	TIE	TIE,TEK	2 Ig-like, 1 EGF, and 3 FNIII-like domains
XII	RYK	RYK	1 transmenbrane b chain linked with one extracellular a chain
XIII	DDR	DDR1, DDR2	1 discoidin-like domain
XIV	RET	RET	1 cadherin-like domain
XV	ROS	ROS	6 FNIII-like domains
XVI	LTK	LTK, ALK	1 cysteine-rich domain
XVII	ROR	ROR1, ROR2	1 Ig-domain, 1 cysteine-rich domain and one kringle-like domains
XVIII	MUSK	MUSK	4 Ig-like and 1 cysteine-rich domains
XIX	LMR	AATYK1, AATYK2, AATYK3	A short extracellular domain
XX	Undetermined	RTK106	A short receptor chain with a short extracellular domain
Human non receptor tyrosine kinases:72-76
I	ABL	ABL1, ABL2 (ARG)	Tyrosine Kinase Domain
II	ACK	TNK1, TNK2 (ACK1)	CRIB (Cdc42/Rac Interactive Binding) Domain
III	CSK	CSK, MATK	SH3 (Src Homology 3) Domain
IV	FAK	PTK2 (FAK). PTK2B (PYK2)	Proline-rich Domains (PRR)
V	FES	FER, FES	F-BAR (FES-CIP4 Homology-Bin-Amphiphysin-Rvs) Domain
VI	FRK	FRK, PTK6 (BRK), SRMS	SH3 (Src Homology 3) Domain, SH2 (Src Homology 2) Domain
VII	JAK	JAK1, JAK2, JAK3,TYK2	Pseudo-Kinase (JH2) Domain
VIII	SRC-A	FGR, FYN, SRC, YES1	SH4 (Src Homology 4) Domain
IX	SRC-B	BLK, HCK, LCK, LYN	Tyrosine Kinase (Catalytic) Domain
X	TEC	BTK, ITK, TEC, TXK	PH (Pleckstrin Homology) Domain, TH (Tec Homology) Domain
XI	SYK	SYK, ZAP70	N-terminal Tandem SH2 (Src Homology 2) Domains

 

 

4.1 Herbal bioactives for Rheumatoid Arthritis (RA): After thousands of years of development and accumulation of clinical experience, herbal medicine has formed a unique theoretical system. Herbal bioactives usually contain a variety of active ingredients, providing an excellent source for the discovery of anti-inflammatory and analgesic drugs. The molecular structures of these compounds are illustrated in Fig. 6.

4.1.1 Curcumin (Curcuma longa): Curcuma longa (Mol. Formula: C₂₁H₂₀O₆ and a molecular weight: 368.38 g/mol.) contains curcumin, a naturally occurring polyphenol molecule with potent anti-inflammatory and antioxidant properties ⁷⁷. According to modern pharmacology, curcumin is a beneficial active ingredient for the prevention and treatment of arthritis. It has been demonstrated that curcumin inhibits the activity of a number of tyrosine kinases, including JAK1/2 and Src. Pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β are produced as a result of intracellular signaling cascades that are started by Src and JAK kinases and contribute to the pathophysiology of RA ⁷⁸. Curcumin, the active component of turmeric, has been studied for its interaction with receptor tyrosine kinases (RTKs) in arthritis, particularly in rheumatoid arthritis (RA) and osteoarthritis (OA). Curcumin modulate RTKs, affecting pathways involved in inflammation, immune responses, and cartilage homeostasis. Curcumin inhibits VEGFR-2, reducing angiogenesis and inflammation in synovial tissue, which is a hallmark of rheumatoid arthritis ⁷⁹. EGFR signaling is involved in synovial fibroblast proliferation, which contributes to joint damage in RA. Curcumin down regulates EGFR phosphorylation, leading to reduced fibroblast activity and synovial hyperplasia. PDGFR (Platelet-Derived Growth Factor Receptor) is involved in fibrosis and joint tissue re-modelling. Curcumin interferes with PDGFR-mediated pathways, preventing fibrosis and joint destruction. FGFR (Fibroblast Growth Factor Receptor) signaling contributes to cartilage degradation in OA ⁸⁰. Curcumin inhibits FGFR activation, reducing cartilage breakdown and promoting chondroprotection. Insulin-like Growth Factor Receptor (IGF-1R) is important for chondrocyte survival and joint repair. Curcumin may help balance IGF-1R signaling, promoting cartilage repair while reducing inflammation ⁸¹. Apart from these, Curcumin blocks downstream signaling of RTKs, such as MAPK, PI3K/Akt, and NF-κB, leading to reduced inflammation. From these, it has been observed and concluded that, Curcumin may slow cartilage degradation and promote repair, suppresses aggressive synovial fibroblast proliferation, reducing pannus formation in RA. While preclinical studies support its benefits, further clinical trials are needed to establish its effectiveness as a targeted RTK inhibitor in arthritis therapy ⁸².

4.1.2 Berberine: Plants including Coptis chinensis (goldenseal) and Berberis vulgaris (barberry) contain Berberine (Mol. Formula: C₂₀H₁₈NO₄ and molecular weight: 336.367 g/mol.), naturally occurring alkaloid that has drawn interest as a possible immunomodulatory and anti-inflammatory treatment for RA. The signal transduction of cytokines such as IL-6, IL-1, and TNF-α depends on JAK2, which is a part of the JAK-STAT pathway. It also lowers the activity of downstream signaling proteins including STAT3, which is important in the transcription of genes linked to inflammation and immunological responses in RA, by blocking JAK2 and Src ⁸³. Berberine affects the immune system and indirectly lowers the inflammatory responses by activating AMPK. Additionally, its activation controls NF-κB, which reduces inflammation in RA.A naturally occurring isoquinoline alkaloid (Berberine) has demonstrated potential in regulating receptor tyrosine kinases (RTKs) implicated in the pathophysiology of rheumatoid arthritis (RA) ⁸⁴.  By blocking important RTKs including vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), it suppresses pathological angiogenesis and synovial hyperplasia, two factors that lead to joint inflammation and injury.  Berberine also inhibits RTK-mediated signalling pathways, such as PI3K/Akt and MAPK, which lowers the production of inflammatory cytokines and the proliferation of fibroblast-like synoviocytes ⁸⁵.  Additionally, it alters insulin-like growth factor 1 receptor (IGF-1R) signalling, which encourages hyper proliferative synoviocytes to undergo apoptosis and stops the thickening of the synovium. These effects demonstrate berberine's anti-inflammatory, anti-angiogenic, and anti-proliferative properties, which make it a viable option for treating RA via modulating RTK ⁸⁶.

4.1.3 Ginseng (Ginsenosides): Ginseng (Panax ginseng, Panax quinquefolius) is a well-known medicinal herb with potent anti-inflammatory, immunomodulatory, and antioxidant properties ⁸⁷. A recent study shows that it can block tyrosine kinase, which may help to treat rheumatoid arthritis (RA).Tyrosine kinases (TKs) are crucial in immune signaling, inflammation, and synovial fibroblast activation in RA. It is a well-liked herbal treatment that helps the body deal with stress because of its adaptogenic qualities. The active ingredients in ginseng, called ginsenosides (Mol. formula: C₄₂H₇₂O₁₄ and a molecular weight: 801.01 g/mol.), block the signalling pathways for MAPK (mitogen-activated protein kinase) and JAK/STAT ⁸⁸. Ginseng, a well-known herbal medicine rich in ginsenosides, has demonstrated potential in modulating receptor tyrosine kinases (RTKs) involved in rheumatoid arthritis (RA). It has been demonstrated that several ginsenosides, including Rg1 and Rb1, interact with RTKs such as vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), suppressing angiogenesis and synovial hyperplasia, two important pathogenic characteristics of RA.  Furthermore, ginseng suppresses downstream signalling pathways controlled by RTK, such as PI3K/Akt and MAPK, which lowers the production of inflammatory cytokines and fibroblast-like synoviocyte proliferation ⁸⁹.  Ginseng prevents excessive synovial thickening by promoting apoptosis in hyper proliferative synoviocytes through modulation of the insulin-like growth factor 1 receptor (IGF-1R).Additionally, ginseng can indirectly control the JAK/STAT pathway through RTK, which lowers levels of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β.  These combined results imply that ginseng may have anti-inflammatory, anti-angiogenic, and anti-proliferative properties through RTK regulation, making it a promising natural treatment agent for RA ⁹⁰.

4.1.4 EpigallocatechinGallate (EGCG): The main catechin in green tea (Camellia sinensis), epigallocatechin gallate (Mol. formula: it C₂₂H₁₈O₁₁ and a molecular weight: 458.37 g/mol.), has shown potent anti-inflammatory, immunomodulatory, and antioxidant qualities. Tyrosine kinase inhibition partially mediates its actions in RA, making a promising natural chemical for RA treatment. Epigallocatechin-3-gallate (EGCG) inhibited the production of osteoclasts by preventing the activation of RANKL, which in turn prevented the development of osteoblasts ⁹¹. The expression of nuclear factor-activated T cells c1, a transcription factor necessary for osteoclast development, is down regulated by RANKL of the JNK and NF-kB pathways. Patients suffering from RHA are unable to stop synovial fibroblasts from dying. Treatment with EGCG has been shown to increase sensitivity to synovial fibroblast apoptosis by suppressing the expression of myeloid cell leukemia -1 ⁹². The main catechin in green tea, epigallocatechin gallate (EGCG), has been demonstrated to interact with receptor tyrosine kinases (RTKs) implicated in the pathophysiology of rheumatoid arthritis (RA).  By blocking important RTKs including vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), EGCG reduces synovial hyperplasia and pathological angiogenesis, two processes that lead to joint inflammation and degeneration ⁹³.  Furthermore, EGCG inhibits RTK-mediated signalling pathways, including as PI3K/Akt and MAPK, which results in decreased fibroblast-like synoviocyte proliferation and pro-inflammatory cytokine production.  Additionally, by modifying the insulin-like growth factor 1 receptor (IGF-1R), it encourages hyperactive synoviocytes to undergo apoptosis and inhibits excessive synovial thickening ⁹⁴. EGCG further reduces inflammatory mediators like TNF-α, IL-6, and IL-1β by indirectly influencing the JAK/STAT pathway through RTK crosstalk.  Because of these combined actions, EGCG is a viable natural therapy candidate for RA through RTK regulation, highlighting its potential as an anti-inflammatory, anti-angiogenic, and anti-proliferative drug ⁹⁵.

4.1.5 Withaferin A: The bioactive compound derived from Withania somnifera (Ashwagandha), exhibits potent anti-inflammatory and immunomodulatory effects, making it a promising bioactive for managing rheumatoid arthritis (RA) through tyrosine kinase inhibition ⁹⁶. Tyrosine kinase inhibition makes Withaferin A (Mol. formula: C₂₈H₃₈O₆ and molecular weight: 470.606 g/mol.), a bioactive molecule extracted from Withania somnifera (ashwagandha), a prospective treatment option for rheumatoid arthritis (RA), due to its strong anti-inflammatory and immunomodulatory properties. Tyrosine kinases such spleen tyrosine kinase (Syk), Janus kinase (JAK), and Src family kinases are essential for immune cell activation, cytokine generation, and synovial fibroblast proliferation in the pathophysiology of RA ⁹⁷. RTKs play a crucial role in the pathogenesis of RA by mediating signaling pathways that drive inflammation, synovial hyperplasia, and joint destruction.By blocking RTK phosphorylation and downstream signalling cascades, including the PI3K/Akt and MAPK pathways, withaferin A inhibits the generation of pro-inflammatory cytokines and the proliferation of fibroblast-like synoviocytes ⁹⁸. Withaferin A also has anti-angiogenic qualities, which help to lessen pannus development and synovial inflammation in RA. Its potential as a natural medicinal drug for modifying RTK-mediated degenerative processes in rheumatoid arthritis is highlighted by these pathways ⁹⁹.

4.1.6 Boswellic acids: Boswellic acids (mol. formula: C₃₀H₄₈O₃ and a molecular weight: 456.7 g/mol.) are the active compounds found in Boswellia serrata (also known as Indian frankincense). These are known for anti-inflammatory, pain-relieving, and immune-modulating properties, making them essential for managing conditions like arthritis and inflammatory diseases ¹⁰⁰.The production of pro-inflammatory cytokines in RA is dependent on JAK-STAT signaling, which is inhibited by Boswellic acids. They lessen the activation of important inflammatory mediators by inhibiting this route. Additionally, it inhibits 5-lipoxygenase, an enzyme that catalyses the synthesis of leukotrienes, inflammatory mediators that exacerbate joint discomfort and damage in RA. Boswellic acids decrease the release of cytokines including TNF-α, IL-6, and IL-1β by inhibiting JAK-STAT and 5-LOX, which helps to lessen pain and inflammation ¹⁰¹. RTKs including the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR) are involved in angiogenesis, joint degeneration, and synovial inflammation in RA.   By altering phosphorylation events, boswellic acid suppresses RTK signalling and lowers the activation of downstream pathways like PI3K/Akt and MAPK, which are implicated in synovial proliferation and inflammatory responses ¹⁰².  Boswellic acid reduces joint inflammation and stops the progression of RA by targeting RTKs and having anti-inflammatory and anti-proliferative actions.  By interfering with important signalling cascades that cause inflammation and tissue damage, boswellic acid has the potential to be used as a natural medicinal drug to manage RA ¹⁰³.

 

 

                                                  

                                                 a.) Curcumin                                                                                       b.) Berberine

                       

     c.) Ginsenosides                                                                        d.) Epigallocatechin Gallate

                                     

                                 e.) Withaferin A                                                                        f.) Boswellic acids

                             

                      g.) Genistein                                                                                    h.) Resveratrol

Figure 6: Chemical structure of tyrosine kinase mediated herbal bioactive with anti-arthritic effect (fig. a; Curcumin, b; Berberine, c; Ginsenosides, d; Epigallocatechin Gallate, e; Withaferin A, f; Boswellic acid is used for RA and fig. g; Genistein, h; Resveratrol is used for OA).

 

 

4.2 Herbal bioactive for Osteoarthritis (OA): Tyrosine kinase pathways may be inhibited by herbal bioactives, offering an alternative to conventional OA therapies. Herbal bioactive substances that target tyrosine kinase pathways have demonstrated potential in the treatment of osteoarthritis (OA). These substances mainly work by altering signalling pathways linked to inflammation and cartilage deterioration. Here are the number of herbal bioactives and their possible function in TK targeting for OA treatment. 

4.2.1 Genistein: Genistein (Mol. formula: C₁₅H₁₀O₅and a molecular weight: 270.240 g·mol⁻¹), a soy-derived isoflavone, exhibits potent anti-inflammatory, chondroprotective, and antioxidant effects, making it a promising therapeutic agent for osteoarthritis (OA) ¹⁰⁴. Genistein exerts its protective effects through the inhibition of Epidermal Growth Factor Receptor (EGFR) and Src Tyrosine Kinase also it suppresses the Focal Adhesion Kinase (FAK) and PI3K/Akt Pathway ¹⁰⁵. Additionally, it inhibits topoisomerase II, which damages DNA and causes cancer cells to undergo apoptosis. It alters a number of signalling pathways that are implicated in inflammation, apoptosis, and cell cycle control, such as PI3K/Akt and NF-κB. Because of these various effects, genistein has been researched for possible advantages in osteoporosis, cardiovascular health, cancer prevention, and neuroprotection ¹⁰⁶. By blocking important RTKs such as vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), it lowers pathological angiogenesis and synovial hyperplasia, two factors that lead to joint inflammation and injury.  Furthermore, genistein suppresses the synthesis of pro-inflammatory cytokines and reduces the proliferation of fibroblast-like synoviocytes by down regulating RTK-mediated signalling pathways, such as PI3K/Akt and MAPK ¹⁰⁷.  Additionally, it inhibits the insulin-like growth factor 1 receptor (IGF-1R), which encourages hyper proliferative synoviocytes to undergo apoptosis and stops excessive synovial thickening.  Additionally, genistein indirectly affects the JAK/STAT pathway through RTK crosstalk, which lowers levels of inflammatory mediators like TNF-α, IL-6, and IL-1β ¹⁰⁸.  Because of these combined actions, genistein is a viable natural therapy candidate for RA through RTK regulation, highlighting its potential as an anti-inflammatory, anti-angiogenic, and anti-proliferative drug ¹⁰⁹.

4.2.2 Resveratrol: Resveratrol (Mol. formula: C₁₄H₁₂O₃ and a molecular weight of approximately 228.24 g/mol.), a polyphenol compound found in grapes, berries, and red wine, exhibits potent chondroprotective and anti-inflammatory properties in osteoarthritis (OA) by modulating tyrosine kinase signaling pathways ¹¹⁰.Resveratrol prevents cartilage degradation and preserves the extracellular matrix by inhibiting EGFR phosphorylation, which in turn lowers the expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-13).RTKs are essential for cell signalling pathways that control immunological responses, inflammation, and RA-related synovial hyperplasia ¹¹¹.   Resveratrol works therapeutically by preventing RTK activation, which in turn down regulates downstream signalling cascades such the PI3K/Akt and MAPK pathways, which are in charge of synovial fibroblast proliferation and the production of inflammatory cytokines.   Resveratrol efficiently lowers bone erosion, cartilage deterioration, and joint inflammation in RA by modifying these pathways ¹¹².  Its anti-inflammatory and antioxidant qualities also aid in reducing oxidative stress and immunological dysregulation linked to the illness.  Therefore, resveratrol's interaction with RTKs offers a viable path for the creation of new RA therapies that focus on the main molecular processes that underlie the course of the illness ¹¹³.

5. Drugs currently investigated in clinical trials: 

We are gathering the data as of February 2025; clinical trials specifically investigating receptor tyrosine kinase (RTK)-mediated herbal bioactives for arthritis treatment are limited. There are the numbers of artificial small-molecule inhibitors that target RTKs specifically, Bruton's tyrosine kinase (BTK) are being studied in clinical settings for RA.

5.1 Poseltinib: An investigational Bruton's tyrosine kinase inhibitor called poseltinib (HM71224, LY3337641) is used to treat rheumatoid arthritis. The Hanmi Pharmaceutical has created it and Eli Lilly was granted a license to use it.In August 2016, rheumatoid arthritis patients started participating in phase II clinical studies ¹¹⁴. There are some plans to conduct more phase II trials to treat immunological disorders such as Sjogren's disease, lupus, and lupus nephritis. Poseltinib is inhibiting the BTK, an essential enzyme in the B-cell receptor (BCR) signalling pathway. BTK is in charge of myeloid and B cell activation, which results in the production of inflammatory cytokines, it also helps to lower the inflammation and immune system over activity in conditions like RA by inhibiting BTK ¹¹⁵. Poseltinib has not yet received approval for clinical usage and is still undergoing clinical research.

5.2 RN486: RN486 is a potent and selective BTK inhibitor identified through structure-based drug design ¹¹⁶. In rat models of inflammatory arthritis, preclinical research has shown dose-dependent efficacy and the potential to reduce B cell and myeloid cell-mediated aspects of the disease. A powerful and selective Bruton's tyrosine kinase (BTK) inhibitor, RN486 was created to treat autoimmune illnesses such as rheumatoid arthritis (RA). In B-cell receptor (BCR) signalling, BTK is an essential enzyme that plays a vital role in B-cell activation and cytokine release ¹¹⁷. In order to reduce inflammation and immunological over activation without completely inhibiting the immune system, RN486 was created to specifically inhibit BTK. In rat models of inflammatory arthritis, preclinical research has shown that RN486 is effective in reducing tissue damage and joint inflammation in a dose-dependent manner ¹¹⁸. 

 

 

     

 a. Poseltinib  b. RN486

Figure 7: Chemical structures of drugs currently investigated under clinical trials.

 

6. List of Chinese herbs targeted to RTKs: 

Receptor Tyrosine Kinase (RTKs) is significant targets in arthritis because of their involvement in inflammation, synovial growth, and angiogenesis ¹¹⁹. There are various Chinese herbs and their bioactive components have been investigated for the effects on modulating RTKs (including VEGFR, EGFR, PDGFR, and FGFR) in arthritis-related disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). Here are the different types of Chinese herbs that have recognized or possible activity in targeting RTK:

 

 

Table 4: Chinese Herbs and Compounds Targeting RTKs in Arthritis

Herb	Active Compound(s)	Target RTK(s)	Mechanism / Effect
Scutellaria baicalensis (Huang Qin)	Baicalin, Baicalein	EGFR, VEGFR	Anti-inflammatory and anti-angiogenic; decreases downstream pathways and RTK phosphorylation
Salvia miltiorrhiza (Dan Shen)	Tanshinone IIA	VEGFR, PDGFR	By blocking RTKs and the PI3K/Akt pathway, it inhibits angiogenesis and synovial hyperplasia.
Glycyrrhiza uralensis (Gan Cao)	Glycyrrhizin, Licochalcone A	EGFR, FGFR	Anti-inflammatory; indirectly modifies RTK signalling
Tripterygium wilfordii (Lei Gong Teng)	Triptolide	EGFR, PDGFR	Potent immunosuppressive and anti-inflammatory properties; blocks RTK-mediated pathways
Epimedium spp. (Yin Yang Huo)	Icariin	VEGFR, PDGFR	Anti-osteoclastic, inhibits RTK to decrease inflammation and angiogenesis
Paeonia lactiflora (Bai Shao)	Paeoniflorin	VEGFR	Prevents the generation of inflammatory cytokines and synovial angiogenesis
Corydalis yanhusuo (Yan Hu Suo)	Tetrahydropalmatine	EGFR	Uses the RTK and MAPK pathways to alter pain and inflammation.
Ligusticum chuanxiong (Chuan Xiong)	Ligustilide, Ferulic acid	VEGFR	Prevents the growth of endothelial cells and neovascularisation

 

                       a. Baicalin                                                                                              b. Tanshinone IIA

                                                                           

                                               c. Glycyrrhizin                                                                                 d. Triptolide

 

                                                             e. Icariin                                                          f. Paeoniflorin

                      

                                                       g. Tetrahydropalmatine                                h. Ligustilide

Figure 8: Chemical structures of Chinese herbs targeted to RTKs.

 

Scutellaria baicalensis has baicalin and baicalein rich compound, lowers the activity of EGFR and VEGFR, resulting in diminished synovial inflammation and blood vessel growth ¹²⁰. Salvia miltiorrhiza has tanshinone IIA, which focuses on VEGFR and PDGFR to prevent neovascularization and the growth of synovial fibroblasts by disrupting the PI3K/Akt pathway¹²¹. Glycyrrhiza uralensis, containing glycyrrhizin and licochalcone A, indirectly influences RTK pathways like EGFR and FGFR, aiding its anti-inflammatory and tissue-protective properties¹²².

 

 

Tripterygium wilfordii (Lei Gong Teng)   Triptolide Modulates EGFR, PGFFR pathways

Epimedium spp. (Yin Yang Huo) Icanin

Glycyrrhizu uralensis (Gan Cao) Triptolide Downregulates EGFR, PDGFR signalling

Salvia miltiorhiza (Dan Shen) Targetes VEGFR, PDGFR

Scutellaria balcalensis (Huang Oin) Down-regulates EGFR, VEGFR Activity

 

Figure 9: Chinese herbs and their bioactives targeted to RTKs

 

Tripterygium wilfordii, via triptolide, demonstrates strong immunosuppressive effects by inhibiting EGFR and PDGFR-related signaling, reducing inflammation and joint damage. ¹²³ Epimedium species, especially because of icariin, reduce VEGFR and PDGFR activity, thereby restricting osteoclast development, blood vessel formation, and cartilage breakdown¹²⁴. Paeonia lactiflora functions via paeoniflorin to decrease VEGFR-driven angiogenesis and cytokine production in synovial tissue¹²⁵. Corydalis yanhusuo, containing tetrahydropalmatine, influences EGFR-related pathways, providing anti-inflammatory and pain-relieving advantages¹²⁶.  Ligusticum chuanxiong, which contains ligustilide and ferulic acid, inhibits VEGFR-induced endothelial growth, aiding in the decrease of synovial neovascularization and joint inflammation¹²⁷. Collectively, these herbs offer a multi-faceted strategy for arthritis treatment through the modulation of RTK signaling pathways. 

7. Challenges and Future Perspectives: 

In recent years, the new insights on pathogenesis of arthritis has found, including the evidence of a persistent state of autoimmune disorder arthritis in affected joints, opened novel possible fields of research. This, together with recent data from herbal bioactives combination trials and biological drugs, led to new possibilities in potential therapeutic approach to RA and OA. The use of receptor tyrosine kinase (RTK)-mediated herbal bioactives for arthritis treatment presents both significant potential and notable challenges. One of the primary challenges in using herbal bioactives for receptor tyrosine kinase (RTK)-mediated arthritis treatment is their poor bioavailability and pharmacokinetics, as many herbal compounds, including resveratrol and withaferin A, suffer from rapid metabolism and limited systemic absorption, reducing their therapeutic efficacy. Additionally, the lack of standardization and quality control in herbal formulations poses a challenge, as variations in extraction methods and plant sources lead to inconsistencies in bioactive concentrations. Furthermore, as most research is limited to preclinical models with few human trials, these bioactives are not commonly recognized as standard arthritis treatments due to a lack of clinical proof and regulatory obstacles, rather than using single-targeted therapy, combination methods are required due to the intricate pathophysiology of arthritis, which involves several inflammatory and oxidative stress pathways. Developing cutting-edge drug delivery methods like liposomal formulations and nanoparticles to improve bioavailability, combining herbal bioactives with traditional arthritis treatments for synergistic effects, and applying precision medicine techniques to customize therapies based on patient-specific biomarkers are some future perspectives. To prove the safety, effectiveness, and standardized dosage of these herbal treatments, more clinical studies and regulatory clearances are also necessary.

8. Conclusion and future perspective:

Herbal bioactives have emerged as prospective therapeutic agents for the treatment of autoimmune arthritis, with anti-inflammatory, immunomodulatory, and chondroprotective properties. Curcumin, resveratrol, quercetin, epigallocatechin gallate (EGCG), and boswellic acids have shown efficacy in preclinical and clinical research by targeting major inflammatory pathways like NF-κB, JAK/STAT, and MAPK signaling. These bioactives not only reduce symptoms, but they also assist modulate immune responses, slowing disease development and preventing joint damage. Despite their potential, problems still exist, including as bioavailability issues, herbal formulation uniformity, and long-term safety assessments. Future research should focus on optimizing delivery methods, which include Nanotechnology-based formulations, such as liposomes, nanoparticles, and micelles, can improve the solubility, stability, and absorption of bioactives like curcumin and resveratrol, hence increasing their therapeutic potential. Current research on synergistic herbal formulations suggests that combination therapy involving different bioactives with complimentary processes may provide increased efficacy while reducing the need for large doses, potentially reducing negative effects. With advances in pharmacogenomics and metabolomics, herbal bioactive treatments can be adjusted to specific genetic and metabolic profiles, resulting in more effective and targeted medicines for autoimmune arthritis patients. Herbal bioactives can be studied as adjunct therapy to traditional treatments such as DMARDs and biologics, with the potential to reduce drug resistance and side effects while enhancing patient outcomes.

List of Abbreviations:

ABL: Alveolar Bone Loss

ACK: Acetate Kinase

ACPAs: Anti-citrullinated protein antibodies 

CCK: cholecystokinin

COX: Cyclooxygenase 

CRIB: Cdc42/Rac Interactive Binding

CSK: C-terminal Src kinase

DMARDs: Disease-modifying anti-rheumatic medications 

EGCG: Epigallocatechin gallate 

EGFR: Epidermal Growth Factor Receptor 

FAK: Focal adhesion kinase

F-BAR: FES-CIP4 Homology-Bin-Amphiphysin-Rvs

FES: Functional electrical stimulation

FGFR: Fibroblast growth factor receptor

FRK: Fyn-related kinase

HGFR: Hepatocyte growth factor receptor

IL-1: Interleukin-1

JAK: Janus-kinase

JH2: Pseudo-Kinase 

JIA: Juvenile Idiopathic Arthritis

LMR: Lymphocyte-to-Monocyte Ratio

LTK: Leukocyte tyrosine kinase

MMPs: Matrix metalloproteinases 

MUSK: Moschus moschiferus

NFκB: NuclearFactor-κB

NGFR: Nerve Growth Factor Receptor

 NSAIDs: Non-steroidal anti-inflammatory drugs 

OA: Osteoarthritis 

PDGFR: Platelet-derived growth factor receptor

PG: Prostaglandin 

PH: Pleckstrin Homology

PRR: Proline-rich Domains

RA: Rheumatoid Arthritis 

RET: Relative enhancement

RF: Rheumatoid factor 

ROR: Retinoic Acid Receptor-Related Orphan Receptor

ROS: Reactive oxygen species

RTKs: Receptor Tyrosine Kinase

SH2: Src Homology 2

SH3: Src Homology 3

SH4: Src Homology 4

SYK: Spleen tyrosine kinase

TEC: Tectorigenin

 TH: Tec Homology

TNF: Tumor necrosis factor

TNF-α: Tumor necrosis factor- alpha

VEGFR: Vascular endothelial growth factor receptor

WHO: World Health Organization

Conflict of interest:  The authors declare no conflicts of interest.

Funding: We have not received any kind of funding from private /Govt./other organizations to complete this manuscript.

Declaration of generative AI and AI-assisted technologies in the writing process: The author(s) used Chat AI to improve the manuscript’s readability and language. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Acknowledgments: The authors are thankful to the principal and management of the Columbia Institute of Pharmacy, Vill. Tekari, Near Vidhansabha Raipur (C.G.) India for providing the necessary facilities to complete the manuscript

Author’s Contributions:

Trilochan Satapathy: Review and Proof reading.

Nikita Patel: Conceptualization, Writing – original draft preparation

Poonam Sahu: Review and Proof reading

Pratibha Dhiwar: Visualization

Kamaksha Tiwari: Grammar Correction

Laxmi Sahu: Tables and Figures

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