An exhaustive examination of the research progress in identifying potential JAK inhibitors from natural products: a comprehensive overview.

JAK family members share extensive homologous domains, which leads to pan-inhibitory activity of many natural compounds against JAKs, making it extremely challenging to discover inhibitors targeting specific JAK members. However, subtle differences exist in the three-dimensional structures among JAK family members. Although different natural compounds exhibit pan-inhibitory activity, they demonstrate varying inhibitory potency against distinct JAK kinases. These characteristics will help guide the modification of these natural compounds to enhance their selectivity, providing significant value for directing drug development. A collection of 20 natural multi-target inhibitors with known structures is present (Table  7 ). These natural compounds span diverse chemical classes, including terpenes, polyphenols, phenylpropanoids, steroids, polyethers and alkaloids. Most concurrently modulate two distinct JAK kinase classes, enabling broad therapeutic applicability beyond single-target inhibition. Below we present the targets of these natural products (Fig.  5 ). Table 7 Potential multi-targets inhibitors with known chemical structures from natural products Candidates CAS number Chemical structures Species Classifications IC 50 Signaling pathways/Targets Pharmacologic effects/applications Geraniol 106–24-1 Lavandula angustifolia Mill Monoterpenes – CHRM3; PRKCA; PRKCD; JAK1/2 Alzheimer’s disease 3-O-methylthespesilactam - Thespesilactam Sesquiterpenes JAK1:1.80 μM; TYK2:2.72 μM JAK1/TYK2-STAT3; JAK2/3-STAT3 Melanoma Triptolide 38,748–32-2 Tripterygium wilfordii Hook F Diterpenes JAK1: < 100 nM; JAK2: < 100 nM EGFR; JAK1/2-STAT1/3 Ankylosing spondylitis; NSCLC Darutigenol 5940–00-1 Sigesbeckia orientalis L Diterpenes – JAK-STAT3 Arthritis Crocin 42,553–65-1 Crocus sativus L Diterpenes JAK1: 10–20 μM; JAK2: 10–20 μM JAK1/2/Src-STAT3 Multiple myeloma cells Betulinic acid 472–15-1 Acacia auriculiformis Benth Triterpenes – JAK2/3-STAT3; ABL1; GSK-3α/β Leukemic Curcumin 458–37-7 Curcuma longa L Polyphenols JAK1: 20 μM; JAK2: < 50 μM JAK2-STAT3; JAK1-STAT5 Acute myeloid leukemia; Colitis; Primary effusion lymphoma growing Resveratrol 501–36-0 Curcuma longa L.; Arachis hypogaea L Polyphenols JAK1: < 30 μM; JAK2: < 50 μM JAK1/3-STAT5; JAK1/2/TYK2-STAT3/5 T-cell acute lymphoblastic leukemia; Myeloproliferative neoplasms; RCC Piceatannol 10,083–24-6 Curcuma longa L.; Arachis hypogaea L Polyphenols JAK1: < 20 μM JAK1-STAT1/3 Atopic dermatitis Kaempferol 520–18-3 Kaempferia galanga L Polyphenols – JAK1/2/Src-STAT3; SHP-1 Atopic dermatitis; Pancreatic cancer Luteolin 491–70-3 Reseda odorata L Flavonoids JAK1: < 12.5 μg/mL JAK1-STAT6; SOCS1; JAK2-STAT3 Ulcerative colitis; Atopic dermatitis Genistein 446–72-0 Glycine max (L.) Merr Flavonoids JAK2: < 40 μM JAK1/2-STAT3; SOCS3 Esophageal-carcinoma; Ulcerative colitis; Liver fibrosis Amorfrutin A 80,489–90-3 Amorpha fruticosa L Flavonoids JAK1: < 40 μM; JAK2: < 40 μM JAK1/2/Src-STAT3 Cervical cancer; Colon cancer; Breast cancer Agerarin – Ageratum houstonianum Mill Chromenes JAK1: 0.473 μM; JAK2: 4.92 μM; JAK3: 3.12 μM JAK1/2 -STAT3 Atopic dermatitis Fraxinellone 28,808–62-0 Dictamnus dasycarpus Turcz Furanones JAK1: < 30 μM; JAK2:  2000 μM; JAK2:9.51 μM; JAK3:25.2 μM; TYK2:667 μM JAK2/3-STAT3; NF-κB Arthritis Koreanaside A – Forsythia koreana (Rehder) Nakai Lignans JAK1: < 40 μM; JAK2: < 40 μM JAK1/2- STAT1/3; NF-κB Colitis Physalin A 23,027–91-0 Alkekengi officinarum var. franchetii (Mast.) R.J.Wang Steroids JAK2: < 5 μM; JAK3: < 5 μM JAK2/3-STAT3 NSCLC; HCC Salinomycin 53,003–10-4 Streptomyces albus Polyethers JAK1: < 10 μM; JAK2: < 10 μM JAK1/2-STAT1/3 Breast cancer Matrine 519–02-8 Sophora flavescens Aiton Alkaloids – JAK2-STAT3 Cholangiocarcinoma Fig. 5 Potential multi-targets inhibitors with their targets. The chemical structures of the 17 compounds and their targets of action are shown on the axes according to the chronological order of the compounds in the research field of targeting JAK kinases. JAK, Janus kinase Potential multi-targets inhibitors with known chemical structures from natural products Geraniol 106–24-1 3-O-methylthespesilactam - Triptolide 38,748–32-2 Darutigenol 5940–00-1 Crocin 42,553–65-1 Betulinic acid 472–15-1 Curcumin 458–37-7 Resveratrol 501–36-0 Curcuma longa L.; Arachis hypogaea L Piceatannol 10,083–24-6 Curcuma longa L.; Arachis hypogaea L Kaempferol 520–18-3 JAK1/2/Src-STAT3; SHP-1 Luteolin 491–70-3 JAK1-STAT6; SOCS1; JAK2-STAT3 Genistein 446–72-0 Amorfrutin A 80,489–90-3 JAK1: < 40 μM; JAK2: < 40 μM Agerarin – Fraxinellone 28,808–62-0 Notopterol 88,206–46-6 Koreanaside A – JAK1: < 40 μM; JAK2: < 40 μM Physalin A 23,027–91-0 JAK2: < 5 μM; JAK3: < 5 μM Salinomycin 53,003–10-4 JAK1: < 10 μM; JAK2: < 10 μM Matrine 519–02-8 Potential multi-targets inhibitors with their targets. The chemical structures of the 17 compounds and their targets of action are shown on the axes according to the chronological order of the compounds in the research field of targeting JAK kinases. JAK, Janus kinase Geraniol, a monoterpene alcohol with a pleasant aroma, is widely distributed in the Fabaceae family. Researches have shown that geraniol had varieties of pharmacological activities, such as anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities [ 153 – 155 ]. Alzheimer’s disease (AD), a neurodegenerative disease with incompletely understood pathogenesis, may involve JAK1 and JAK2 as therapeutic targets of geraniol [ 156 ]. Further investigation is required to establish geraniol’s therapeutic potential for AD. 3-O-methylthespesilactam, a 3-O-methyl derivative of thespesilactam, was identified as a novel class of anticancer sesquiterpenes targeting JAK in A2058 human melanoma cells. 3-O-methylthespesilactam inhibited cell viability in human cancer cells and induced apoptosis and S-phase cell-cycle arrest in A2058 melanoma cells [ 157 ]. These findings suggest that 3-O-methylthespesilactam may represent a promising lead compound against human cancer cells. Triptolide (TPL), a bioactive diterpene triperoxide isolated from Tripterygium wilfordii . demonstrated anti-inflammatory, immunosuppressive, and antitumor properties [ 158 ]. JAK1 expression levels correlated with TPL’s cytotoxic response [ 159 ]. Meanwhile, JAK2 was the target of TPL intervention CTD-ILD and TPL could restrain the activation of the JAK2-STAT3 signaling pathway in ankylosing spondylitis [ 160 , 161 ]. In terms of tumor immunity, TPL reduced PD-L1 expression through the EGFR and JAK1/2-STAT1/3 signaling pathways in NSCLC cells [ 12 ]. Darutigenol (DL), a diterpenoid derived Sigesbeckia orientalis L., exhibited anti-inflammatory activity [ 162 , 163 ]. DL ameliorated inflammation and cartilage degradation in murine arthritis models via inhibition of JAK-STAT3 pathway, as evidenced through integrated network pharmacology [ 164 ]. Crocin, a bioactive constituent of Crocus sativus L., has been applied as an anodyne, aphrodisiac, and emmenagogue. A study demonstrated that crocin can mediate the suppression of STAT3 and inhibit the upstream kinases JAK1, JAK2, and SRC, thereby preventing the progression of multiple myeloma [ 14 ]. Betulinic acid (BA), a natural pentacyclic triterpene compound, is isolated from Acacia auriculiformis Benth. with anti-inflammatory, antibacterial, antidiabetic, anti-HIV and antitumor effects [ 165 , 166 ]. Study showed that BA could mitigate T-2 toxin-induced testicular injury by reducing germ cell apoptosis through JAK2-STAT3 signaling downregulation [ 167 ]. Betulin, the precursor of betulinic acid, could inhibit JAK3 conferring significant antitumor potential [ 168 ]. Curcumin (diferuloylmethane), a natural yellow polyphenol pigments isolated from the rhizomes of Curcuma longa L., had a wide range of applications, such as playing a synergistic effect on Alzheimer’s disease, antiviral effect, intestinal mucosal barrier function protective effect, anticancer effect [ 169 – 172 ]. Curcumin mitigated acute myeloid leukemia by upregulating p53 pathway and downregulating the JAK2-STAT3 pathway [ 173 ]. Curcumin targeted JAK1 to ameliorate dextran sulfate sodium-induced colitis and inhibit primary effusion lymphoma growth [ 171 , 172 ]. Resveratrol, a naturally occurring polyphenol abundant in grapes, peanuts, red wine and certain plants, exhibits anticancer activity against T-cell acute lymphoblastic leukemia [ 174 ], myeloproliferative neoplasms [ 175 ], renal cell carcinoma [ 176 ] through JAK1and JAK2 inhibition. Moreover, its anti-inflammation effects extended to RAW 264.7 macrophages activated microglia cells and BTBR T autistic mouse models [ 177 – 179 ]. Piceatannol, the metabolite of Resveratrol, attenuated AD by targeting JAK1 and showed higher therapeutic efficacy than resveratrol [ 180 ]. Learned from this, resveratrol has a great potential for structural modifications through which resveratrol improves bio-targeting itself. Kaempferol, a natural plant flavonoid compound is isolated both from kaempferia galanga L. A TCM composite formula, Jiu-Wei-Yong-An formula containing Kaempferol, alleviated AD-like skin lesions through suppressing JAK1-STAT3 and MAPK signaling pathways [ 181 ]. And Kaempferide (KF), a Kaempferol derivative, dose-dependently decreased the phosphorylation of JAK1, Src and STAT3 in the pancreatic cancer cell lines [ 158 ]. Besides, kaempferol downregulated the JAK1-STAT3 signaling pathway by which it inhibited the activation of neutrophils in peripheral blood and their infiltration into the ischemic brain. Paradoxically, Shanshan Zhang et al. reported that kaempferol didn’t inhibit JAK2 in neutrophils. In another research, Kaempferol promoted glucose uptake in myotubes via JAK2 inhibition and was considered as an effective compound for the prevention of hyperglycemia [ 182 , 183 ]. Whether Kaempferol targeting JAK2 is cell-specific needs further validation. Luteolin (LUT), a flavonoid polyphenolic compound ubiquitously present in fruits, vegetables, flowers, and herbs. demonstrated anti-inflammatory properties through JAK-STAT pathway modulation. Luteolin-7-O-glucoside alleviated dextran sodium sulfate-induced ulcerative colitis mice by decreasing the secretion of inflammatory factors and reducing inflammatory responses via the JAK1-STAT6-SOCS1 pathway [ 184 ]. Similarly, this pathway also underpinned LUT’s efficacy against long-COVID inflammatory sequelae [ 185 ]. JAK2-STAT3 is possibly another signaling pathway for LUT’s anti-inflammatory property. Combining network pharmacology and experimental validation, Tang Liu et.al confirmed that LUT alleviated AD by inhibiting the JAK2-STAT3 signaling [ 19 ]. Genistein, a phytoestrogen abundant in Glycine max (L.) Merr., showed its diverse bioactivities, including anti-inflammatory, antioxidant, anticancer properties [ 186 – 188 ]. JAK-STAT pathway constitutes a key mechanism underlying these effects. Researches revealed that genistein inhibited the proliferation of esophageal-carcinoma cell and ameliorated acetic acid-induced ulcerative colitis via JAK1/2-STAT3 suppression. Moreover, genistein exhibited hepatoprotective effect on dimethyl nitrosamine induced liver fibrosis models by inhibiting the JAK2-STAT3-SOCS3 signaling pathway [ 189 ]. We could conclude that JAK2-STAT3 played an important role in Genistein’s biological activities. Amorfrutin A, a natural product isolated from the fruits of Amorpha fruticosa L., exhibits documented anti-inflammatory properties through PPARα/γ agonism [ 190 , 191 ]. But the mechanism of anticancer activity of Amorfrutin A was associated with JAK-STAT signaling [ 192 ]. Agerarin, is a bioactive compound derived from the ethanolic extract of Ageratum houstonianum Mill [ 193 ]. Agerarin abrogated IL-4-induced PER2 expression in HaCaT Cells through the JAK-STAT3 signaling pathway and ameliorated skin inflammation especially AD [ 194 ]. Fraxinellone (FRA), a degraded limonoid isolated from the root bark of Dictamnus dasycarpus Turcz., belongs to furanone compounds in chemical structure. FRA had potent insecticidal activity and pro-apoptosis effects in tumor cells [ 195 ]. A study revealed that FRA may inhibit PD-L1 expression via JAK1/2/Scr-STAT3 pathway inhibition [ 196 ]. Currently, FRA has been used as TCM preparations against malignancies in clinic. Notopterol (NOT), a furanocoumarin and primary bioactive component of Hansenia weberbaueriana (Fedde ex H.Wolff) Pimenov & Kljuykov, established efficacy in arthritis management. A research demonstrated that NOT directly bound to JAK2 and JAK3, inhibiting JAK-STAT signaling pathway activation [ 197 ]. And NOT also provided chondroprotective effects against inflammation through JAK2-STAT3 pathway suppression [ 198 ]. Koreanaside A (KA), a lignan isolated from the flowers of Forsythia koreana (Rehder) Nakai, inhibited LPS-induced pro-inflammatory mediators in activated macrophages through JAK1/2 inactivation and subsequent STAT1/3 signaling pathway suppression [ 199 ]. KA also has a significant improvement effect on pathological manifestations of colitis, such as colon shortening, and spleen enlargement, positioning it as a potential therapeutic strategy for colitis. Physalin A, a bioactive withanolide from Alkekengi officinarum var. franchetii (Mast.) R.J.Wang, was reported to exert anti-tumor activity in NSCLC and HCC [ 200 , 201 ]. Physalin A modulated the tyrosine phosphorylation of JAK2 and JAK3 in a dose-dependent manner and abrogated the nuclear translocation and transcriptional activity of STAT3, showing anticancer activity in NSCLC [ 200 ]. But PI3K-AKT signaling pathway was considered to related to physalin A-induced apoptosis and autophagy in HCC [ 201 ]. Salinomycin, a polyether antibiotic produced by Streptomyces albus via tank fermentation, overcomes tumor multidrug resistance by selectively targeting the cancer stem cells, positioning it as a novel chemotherapeutic agent [ 202 ]. Although the underlying mechanisms of the Salinomycin’s anticancer effects remained incompletely characterized, some evidence indicated that salinomycin decreased IFN-γ-induced IDO1 expression in human breast cancer cells through inhibiting the JAK-STAT pathway [ 203 ]. Matrine (MT), a quinolizidine alkaloid isolated from Sophora flavescens Aiton, exhibits broad pharmacological activities, such as anti-inflammatory, antitumor, anti-arrhythmic, antifibrotic, and cardioprotective effects [ 204 – 206 ]. MT suppressed the proliferation in human cholangiocarcinoma cells via inhibition of JAK2-STAT3 signaling pathway [ 207 ]. Oxymatrine (OMT), the oxide derivative of MT, inhibited tumor growth in a lung cancer xenograft model by blocking JAK1, JAK2 and Src kinase activation upstream of STAT5, thereby suppressing STAT5 phosphorylation [ 208 ].

The JAK (Janus Kinase)-STAT (Signal Transducer and Activator of Transduction) pathway functions as a central signaling nexus that coordinates rapid transduction of extracellular signals from membrane receptors to nuclear effectors. The tyrosine kinase family comprises four structurally homologous members, namely JAK1, JAK2, JAK3, TYK2 [ 1 ]. Mechanistic studies have established that dysregulated JAK activity is pathologically implicated in autoimmune disorders and oncogenesis [ 2 ]. Notably, JAK-STAT hyperactivation drives the inflammatory cascade in atopic dermatitis (AD), positioning JAK inhibitors (e.g., tofacitinib, baricitinib) as first-line therapeutic agents for moderate-to-severe AD [ 3 , 4 ]. Similarly, pro-inflammatory and anti-inflammatory cytokines central to rheumatoid arthritis (RA) can be produced additionally through the JAK-STAT pathway, explaining the clinical efficacy of JAK inhibition in RA management [ 5 ]. An overview of diseases correlated with the JAK-STAT pathway and organs where the diseases occur is presented below (Fig.  1 ). Fig. 1 JAK-STAT pathway-associated disorders and their target organ systems. Eight clinically significant disease entities demonstrate established associations with JAK-STAT signaling abnormalities: atopic dermatitis, rheumatoid arthritis, periodontal diseases, hepatocellular carcinoma, non-small cell lung cancer, gastric cancer, chronic kidney disease and colon cancer JAK-STAT pathway-associated disorders and their target organ systems. Eight clinically significant disease entities demonstrate established associations with JAK-STAT signaling abnormalities: atopic dermatitis, rheumatoid arthritis, periodontal diseases, hepatocellular carcinoma, non-small cell lung cancer, gastric cancer, chronic kidney disease and colon cancer Currently approved JAK inhibitors including tofacitinib and baricitinib demonstrate significant clinical efficacy, particularly in managing cutaneous inflammatory disorders. Nevertheless, three clinically significant adverse events—opportunistic infections, acquired drug resistance, and thromboembolic complications—remain critical concerns [ 6 – 8 ]. Therefore, these limitations collectively underscore the critical imperative to engineer next-generation JAK inhibitors with enhanced therapeutic safety. Traditional Chinese medicine (TCM) represents a unique therapeutic paradigm characterized by unparalleled chemical diversity and pharmacological diversity. Accumulating empirical validation through long-term clinical practice has led to growing global recognition of its therapeutic value. Notably, studies have systematically confirmed that TCM-derived agents possess distinct antitumor and immunomodulatory properties [ 9 – 11 ]. Based on this pharmacological foundation, our investigation prioritizes traditional herbal compounds as a strategic resource for JAK inhibitor discovery, aiming to identify novel small-molecule candidates from TCM’s chemically diverse repository.

The objective of this review was to collect comprehensive information about potential JAK inhibitors from natural products. Hot compounds for research got more article length in this paper. For compounds with low expectation, we briefly state the status of the research. Through this review, we hope to provide natural products which can been screened as a therapeutic strategy for researchers and find some patterns that others can refer to. In JAK-STAT signaling pathways, JAK1-STAT3 and JAK2-STAT3 got priority in molecular mechanisms research of potential JAK inhibitors. This can be attributed to extensive involvement of JAK1, JAK2, STAT3 in inflammatory response, immune response, tumorigenesis. In addition, JAK1-STAT5, JAK2-STAT1, JAK3, TYK2 are also directions in which we can promisingly make more progress. In this review, JAK1, JAK2 and multi-target JAK inhibitors take up most of the article but JAK3 and TYK2 inhibitors take up few. We classify the compounds of the former according to their chemical structures, finding most belongs to terpenes and polyphenols. This suggests that these categories are easier to find biologically active ingredients and they deserve more attention. For plant extracts, although we didn’t find any rules that we can utilize in the classification, but most herbs are common medicine of TCM. This echoes what we have said above. These traditional Chinese herbs are a necessary treasure house for us to discover and invent new drugs. According to our investigation, among autoimmune disorders, research hotspots focused on RA, colitis, AD. Among cancers, NSCLC, HCC and colon cancer got more attention. Currently, the clinical translation of these natural JAK inhibitors still faces numerous challenges, with the developability issues of small molecule compounds remaining unresolved. Due to limited reported data on ADME properties of natural JAK inhibitors, we utilized a specialized platform ( https://drugflow.com/ ) for predictive analysis (Supplementary Table 1). The predictions revealed that six compounds, including Ouabain and Crocin, exhibited excessive molecular weight, while nearly half showed LogP values outside the desirable range. Ultimately, 19 compounds such as Ouabain and Lycopene were excluded based on Lipinski’s Rule of Five. Additionally, 26 compounds including Lycopene and Ellagic Acid may suffer from low oral bioavailability, half of the compounds (e.g., Calcaratarin D and Cycloastragenol) might have T1/2 < 3 h, and most compounds potentially pose skin sensitization concerns. These results indicate significant challenges in transforming existing natural products into clinical therapeutics. However, we also identified several promising compounds with development potential, such as Igalan, Sanshool, Spilanthol, Geraniol, Fraxinellone, Matrine, and Psoralen, which demonstrate favorable drug-like properties and inhibitory activity, representing the most valuable candidates for clinical translation. Similarly, certain compounds, after proper modification, also hold significant application potential. Throughout this review, we have known that the mechanism of action of many compounds remains to be further clarified and some remains controversial in effects on JAK. These leave the problems we need solve urgently. For drugs with high efficacy and safety, pushing them to the clinic is what we need to do in the medium and long term. We hope that this review will contribute to the discovery and development of new JAK inhibitors.

With documented use spanning millennia, TCM stands as one of humanity’s earliest systematized therapeutic approaches. The integration of TCM’s empirical knowledge with modern target discovery constitutes an efficient discovery paradigm, as evidenced by multiple pharmacological validations. Representative examples include: Tripterygium wilfordii Hook F, historically employed in managing immune-related rheumatic diseases, has demonstrated extended therapeutic value in non-small cell lung cancer (NSCLC) treatment [ 12 ]; Crocus sativus L., historically utilized in Asian anticancer regimens, has yielded the bioactive constituent crocin demonstrating marked efficacy against gastric malignancies [ 13 , 14 ]; Psoralea corylifolia L., a canonical osteoprotective agent, contains isobavachalcone with retained therapeutic efficacy in RA [ 15 , 16 ]; Hypericum perforatum L., traditionally applied for burns, sunburns, and gastric irritation, has been confirmed hypericin-mediated anti-inflammatory property [ 17 , 18 ]; Reseda odorata L., with traditional applications against oxidative stress and acute inflammation, provides luteolin showing clinical potential in ulcerative colitis and AD [ 19 , 20 ]. Mechanistic studies consistently identify JAK inhibition as the unifying pharmacological mechanism underlying these therapeutic outcomes. These cases collectively demonstrate the promise of identifying JAK inhibitors from TCM for broader disease treatment. Current JAK inhibitor discoveries from natural products show uneven distribution across subtypes. Our review found more JAK1 and JAK2 inhibitors than JAK3 and TYK2 inhibitors, possibly due to their different discovery periods. We have categorized these natural products by targets (Fig.  2 ). Fig. 2 Mechanistic classifications of JAK inhibitors derived from TCM. The left panel depicts four flavors of TCM. The center panel depicts potential JAK inhibitors. The right panel depicts the concept of the TCM philosophy. Natural products with known chemical structures can be classified as potential JAK1 inhibitors, potential JAK2 inhibitors, potential JAK3 inhibitors, potential TYK2 inhibitors and potential multiple-targets inhibitors. JAK, Janus kinase; TYK2, Tyrosine kinase 2; TCM, Traditional Chinese medicine Mechanistic classifications of JAK inhibitors derived from TCM. The left panel depicts four flavors of TCM. The center panel depicts potential JAK inhibitors. The right panel depicts the concept of the TCM philosophy. Natural products with known chemical structures can be classified as potential JAK1 inhibitors, potential JAK2 inhibitors, potential JAK3 inhibitors, potential TYK2 inhibitors and potential multiple-targets inhibitors. JAK, Janus kinase; TYK2, Tyrosine kinase 2; TCM, Traditional Chinese medicine

Additional file 1. Additional file 1.