Modifying T cell phenotypes using TYK2 inhibitor and its implications for the treatment of systemic lupus erythematosus.

OBJECTIVES: The tuning effects of JAK/TYK2 inhibitors on the imbalance between T follicular helper (Tfh) and T regulatory (Treg) cells, related to systemic lupus erythematosus (SLE) pathogenesis, were investigated using human peripheral blood samples. METHODS: Peripheral blood mononuclear cells from untreated patients with SLE and healthy controls were analysed. Tfh1 cells were identified in nephritis tissue, and the effect of Tfh1 cells on B-cell differentiation was examined by coculturing naïve B cells with Tfh1 cells. RESULTS: Tfh1 cell numbers were increased in the peripheral blood of patients, and activated Treg cell counts were decreased relative to Tfh1 cell counts. This imbalance in the Tfh to Treg ratio was remarkably pronounced in cases of lupus nephritis, especially in types III and IV active nephritis. Immunohistochemistry revealed Tfh1 cell infiltration in lupus nephritis tissues. Co-culture of Tfh1 cells (isolated from healthy individuals) with naïve B cells elicited greater induction of T-bet+ B cells than controls. In JAK/TYK2-dependent STAT phosphorylation assays using memory CD4+ T cells, IL-12-induced STAT1/4 phosphorylation and Tfh1 cell differentiation were inhibited by both JAK and TYK2 inhibitors. However, phosphorylation of STAT5 by IL-2 and induction of Treg cell differentiation by IL-2+TGFß were inhibited by JAK inhibitors but not by TYK2 inhibitors, suggesting that TYK2 does not mediate the IL-2 signalling pathway. CONCLUSIONS: Tfh1 cells can induce T-bet+ B cell production and may contribute to SLE pathogenesis-associated processes. TYK2 inhibitor may fine-tune the immune imbalance by suppressing Tfh1 differentiation and maintaining Treg cell differentiation, thereby preserving IL-2 signalling, unlike other JAK inhibitors.

Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.

BACKGROUND: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. METHODS: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. RESULTS: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1ß and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. CONCLUSIONS: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines.

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.

RuBi-Ruxolitinib: A Photoreleasable Antitumor JAK Inhibitor.

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.

Reversible effects on female rat fertility with abrocitinib, a Janus kinase 1 inhibitor.

BACKGROUND: Abrocitinib is a Janus kinase (JAK) 1 selective inhibitor approved for the treatment of atopic dermatitis. Female reproductive tissues were unaffected in general toxicity studies, but an initial female rat fertility study resulted in adverse effects at all doses evaluated. A second rat fertility study was conducted to evaluate lower doses and potential for recovery. METHODS: This second study had 4 groups of 20 females each administered abrocitinib (0, 3, 10, or 70 mg/kg/day) 2 weeks prior to cohabitation through gestation day (GD) 7. In addition, 2 groups of 20 rats (0 or 70 mg/kg/day) were dosed for 3 weeks followed by a 4-week recovery period before mating. All mated females were evaluated on GD 14. RESULTS: No effects were observed at ≤10 mg/kg/day. At 70 mg/kg/day (29x human exposure), decreased pregnancy rate, implantation sites, and viable embryos were observed. All these effects reversed 4 weeks after the last dose. CONCLUSIONS: Based on these data and literature on the potential role of JAK signaling in implantation, we hypothesize that these effects may be related to JAK1 inhibition and, generally, that peri-implantation effects such as these, in the absence of cycling or microscopic changes in nonpregnant female reproductive tissues, are anticipated to be reversible.

Small molecule drug discovery targeting the JAK-STAT pathway.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.

Inhibition of the JAK-STAT Pathway in the Treatment of Psoriasis: A Review of the Literature.

Psoriasis is a highly prevalent dermatological disease associated with an increased systemic inflammatory response. In addition, joint involvement is also present in around 20% of patients. Therefore, treatment modalities used in this condition should be simultaneously effective at improving skin manifestations, reducing inflammation, and addressing psoriatic arthritis when present. Twenty years ago, the introduction of biologic treatments for psoriasis was a turning point in the management of this condition, offering an effective and reasonably safe option for patients whose disease could not be adequately controlled with conventional therapies. At the moment, Janus Kinase inhibitors (JAKis) are a new class of promising molecules in the management of psoriasis. They are orally administered and can show benefits in patients who failed biologic therapy. We conducted a scoping review in order to identify randomized-controlled trials that investigated different JAKis in patients with plaque psoriasis and psoriatic arthritis, with an emphasis on molecules that have been approved by the European Medicines Agency and the Food and Drug Administration. The added value of this study is that it collected information about JAKis approved for two different indications, plaque psoriasis and psoriatic arthritis, in order to provide an integrated understanding of the range of effects that JAKis have on the whole spectrum of psoriasis manifestations.

Evaluating the pharmacokinetics of upadacitinib for the treatment of moderate-to-severe Crohn's disease.

INTRODUCTION: Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn's disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety. AREAS COVERED: This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD. EXPERT OPINION: The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation.

BACKGROUND: JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. METHODS: A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-ß1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFß-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. RESULTS: CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1ß and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFß-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-ß1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. CONCLUSION: JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.

Modelling atopic dermatitis in healthy human skin for the characterization of topical compounds.

Suitable human models for the development and characterization of topical compounds for inflammatory skin diseases such as atopic dermatitis are not readily available to date. We describe here the development of a translational model involving healthy human skin mimicking major aspects of AD and its application for the characterization of topical Janus kinase inhibitors. Full thickness human abdominal skin obtained from plastic surgery stimulated in vitro with IL4 and IL13 shows molecular features of AD. This is evidenced by STAT6 phosphorylation assessed by immunohistochemistry and analysis of skin lysates. Broad transcriptome changes assessed by AmpliSeq followed by gene set variation analysis showed a consistent upregulation of gene signatures characterizing AD in this model. Topical application of experimental formulations of compounds targeting the JAK pathway to full thickness skin normalizes the molecular features of AD induced by IL4 and IL13 stimulation. The inhibitory effects of topical JAK inhibitors on molecular features of AD are supported by pharmacokinetic analysis. The model described here is suited for the characterization of topical compounds for AD and has the potential to be extended to other inflammatory skin diseases and pathophysiological pathways.

Ruxolitinib Cream 1.5%: A Review in Non-Segmental Vitiligo.

Topical ruxolitinib 1.5% cream (Opzelura®), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients. Efficacy was sustained in longer-term analyses to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable in these trials; the most common treatment-related adverse events were acne, pruritus and exfoliation, all at the application site. As with orally administered JAK inhibitors, topical ruxolitinib carries boxed warnings in the USA for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis, although the incidences were low with topical application. Thus, topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo.

Non-segmental vitiligo is a chronic autoimmune disease where the skin throughout the body loses its pigmentation, and is usually managed with topical therapies, light therapy or surgery. Topical ruxolitinib 1.5% cream (Opzelura^®) is the first treatment approved in several countries for patients aged ≥ 12 years with non-segmental vitiligo. It inhibits Janus kinase (JAK) proteins, reducing the destruction of skin pigment-producing cells. In two clinical trials, significantly more ruxolitinib cream recipients achieved significant and meaningful skin repigmentation compared with patients who received a non-medicated cream; these results were sustained to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable; the most common treatment-related adverse events were acne, itchiness and exfoliation, all at the application site. Topical ruxolitinib has special warnings in the USA for major adverse cardiovascular events (MACE), blood clots, serious infections, death and cancer (associated with the use of oral JAK inhibitors), although incidence rates for these adverse events were low in the clinical trials. Topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo.

Electrochemical Behavior of Janus Kinase Inhibitor Ruxolitinib at a Taurine-Electropolymerized Carbon Paste Electrode: Insights into Sensing Mechanisms.

Ruxolitinib (RXL) is a Janus kinase inhibitor used for treating intermediate- or high-risk myelofibrosis. This study presents an electrode modified with electrochemically polymerized taurine on a carbon paste electrode via cyclic voltammetry (CV). The surface characterization of the poly(taurine)-CP electrode was evaluated by using electrochemical (electrochemical impedance spectroscopy─EIS, CV), morphological (scanning electron microscope─SEM), and spectroscopic (Fourier-transform infrared spectroscopy─FT-IR) techniques. Under optimized conditions, RXL exhibited good linearity within the 0.01-1.0 µM concentration range, with a limit of detection (LOD) of 0.005 µM. The proposed electrochemical sensor demonstrated excellent selectivity, accuracy, precision, and repeatability. Furthermore, it effectively detected RXL in human urine and pharmaceutical samples.

Novel investigational drugs for alopecia areata and future perspectives.

INTRODUCTION: Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. While acute, solitary patches often spontaneously remit, developing secondary patches or failure of the disease to resolve within 6-12 months predicts a poor prognosis, with an increased risk of alopecia totalis or universalis. Chronic AA increases the risk of depression and suicidality and reduces quality of life. Treatment options for chronic or acute diffuse AA were previously limited to corticosteroids and traditional immunomodulators. Two Janus Kinase (JAK) inhibitors are now approved for the treatment of chronic AA. AREAS COVERED: The results of landmark phase 3 trials for three JAK inhibitors, baricitinib, ritlecitinib, and deuruxolitinib are discussed. Evidence for other JAK inhibitors, biologics, and phosphodiesterase-4 inhibitors are also presented. Therapies currently undergoing clinical trials are listed. EXPERT OPINION: JAK inhibitors are a safe and efficacious treatment of moderate-to-severe AA. Early intervention, regardless of severity, allows for improved treatment efficacy. It is uncertain how long patients should remain on JAK inhibitors; discontinuation often leads to relapse. A black-box warning for JAK inhibitors was extrapolated from safety data in a rheumatoid arthritis cohort; recent meta-analyses of JAK inhibitors used in dermatology cohorts do not demonstrate the same risk profile.

Comprehensive overview of novel chemical drugs for ulcerative colitis: focusing on phase 3 and beyond.

INTRODUCTION: Despite the growing number of highly efficacious biologics and chemical drugs for ulcerative colitis (UC), steroid-free disease control is still difficult to achieve in subgroups of patients due to refractoriness, adverse events, primary or secondary failure. New treatments are therefore still required in order to optimize clinical management of patients with UC. AREAS COVERED: The efficacy and safety of both currently available and newly developed small molecules have been summarized. The PubMed database and clinicaltrials.gov were considered in order to search for phase 2b and 3 trials on new chemical drugs for UC. The study drugs reviewed included Janus kinases (JAK) and sphingosine-1-phosphate receptor (S1Pr) inhibitors, α4 integrin antagonist, and micro-RNA-124 upregulators. EXPERT OPINION: Rapidity of onset, low immunogenicity, and safety are the main characteristics of small molecules currently available or under evaluation for treatment patients with UC. Among the currently available chemical drugs, the selective JAK and the S1Pr inhibitors are characterized by a good safety profile combined with the ability to induce clinical remission in UC. A relatively low frequency of endoscopic improvement and healing currently appears associated with their use, being higher in UC patients treated with S1Pr inhibitor Etrasimod. Overall, additional new safe and effective drugs are still required in order to optimize disease control in a larger majority of UC patients.

Momelotinib in myelofibrosis.

INTRODUCTION: Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. AREAS COVERED: This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients. EXPERT OPINION: Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.

Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

JAK inhibition during the early phase of SARS-CoV-2 infection worsens kidney injury by suppressing endogenous antiviral activity in mice.

Coronavirus disease 2019 (COVID-19) induces respiratory dysfunction as well as kidney injury. Although the kidney is considered a target organ of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and affected by the COVID-19-induced cytokine storm, the mechanisms of renal reaction in SARS-CoV-2 infection are unknown. In this study, a murine COVID-19 model was induced by nasal infection with mouse-adapted SARS-CoV-2 (MA10). MA10 infection induced body weight loss along with lung inflammation in mice 4 days after infection. Serum creatinine levels and the urinary albumin/creatinine ratio increased on day 4 after MA10 infection. Measurement of the urinary neutrophil gelatinase-associated lipocalin/creatinine ratio and hematoxylin and eosin staining revealed tubular damage in MA10-infected murine kidneys, indicating kidney injury in the murine COVID-19 model. Interferon (IFN)-γ and interleukin-6 upregulation in the sera of MA10-infected mice, along with the absence of MA10 in the kidneys, implied that the kidneys were affected by the MA10 infection-induced cytokine storm rather than by direct MA10 infection of the kidneys. RNA-sequencing analysis revealed that antiviral genes, such as the IFN/Janus kinase (JAK) pathway, were upregulated in MA10-infected kidneys. Upon administration of the JAK inhibitor baricitinib on days 1-3 after MA10 infection, an antiviral pathway was suppressed, and MA10 was detected more frequently in the kidneys. Notably, JAK inhibition upregulated the hypoxia response and exaggerated kidney injury. These results suggest that endogenous antiviral activity protects against SARS-CoV-2-induced kidney injury in the early phase of infection, providing valuable insights into the pathogenesis of COVID-19-associated nephropathy.NEW & NOTEWORTHY Patients frequently present with acute kidney injury or abnormal urinary findings after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated how the kidneys respond during SARS-CoV-2 infection using a murine coronavirus disease 2019 (COVID-19) model and showed that Janus kinase-mediated endogenous antiviral activity protects against kidney injury in the early phase of SARS-CoV-2 infection. These findings provide valuable insights into the renal pathophysiology of COVID-19.

The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.