2. Academic Validation
  3. High-throughput screening identifies FDA approved drug mitiglinide as a novel pyroptosis inhibitor and therapeutic agent for osteoarthritis

High-throughput screening identifies FDA approved drug mitiglinide as a novel pyroptosis inhibitor and therapeutic agent for osteoarthritis

  • J Adv Res. 2025 Dec 11:S2090-1232(25)00994-4. doi: 10.1016/j.jare.2025.12.004.
Hanwen Zhang 1,  Tanxin Yu 1,  Nanfang Zhuo 2,  Zongxin Zhu 1,  Shihan Lin 1,  Shiying Zhao 1,  Huilin Yu 1,  Youli Zhang 1,  Aimin Wu 3,  Jiangning Wang 4,  Yifei Zhou 5,  Xiaolei Zhang 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088 Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035 Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China.
  • 2 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China; Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088 Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035 Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China. Electronic address: [email protected].
  • 4 Department of Orthopaedics, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China. Electronic address: [email protected].
  • 5 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088 Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035 Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China. Electronic address: [email protected].
  • 6 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088 Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035 Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325035 Zhejiang Province, China. Electronic address: [email protected].
PMID: 41386507 DOI: 10.1016/j.jare.2025.12.004
Abstract

Introduction: Osteoarthritis (OA), a leading cause of joint dysfunction, is characterized by progressive cartilage degradation linked to chondrocyte Pyroptosis, yet disease-modifying therapies remain elusive. In this study, we conducted the first systematic drug repurposing screen in chondrocytes, aiming at identifying drugs that may suppress Pyroptosis and verifying the therapeutic effects on OA.

Methods: Mitiglinide's effects on chondrocyte viability were quantified via CCK-8 assays and live/dead staining. Pyroptosis inhibition, extracellular matrix (ECM) homeostasis, and NF-κB activation were measured by western blot and immunofluorescence. Network pharmacology analysis and molecular docking were applied to predict the interacting protein of mitiglinide, while Nrf2 was knocked down by siRNAs to confirm its role in mitiglinide regulated Pyroptosis and ECM. In vivo, destabilization of the medial meniscus (DMM) model -induced OA mice received mitiglinide for 8 weeks, with efficacy evaluated through X-ray, OARSI-graded histopathology, immunohistochemistry, Hematoxylin-Eosin and Safranin O-Fast green staining.

Results: Through high-throughput screening (HTS) of 1,228 FDA-approved drugs, we identified a list of Pyroptosis inhibitors, and mitiglinide was suggested as one of the most potent Pyroptosis inhibitors in chondrocyte. Mechanistic studies demonstrated that mitiglinide may directly target Nrf2 and suppress its downstream NF-κB-driven NLRP3 inflammasome activation; it may also promote ECM homeostasis in chondrocytes. In vivo study showed that mitiglinide may effectively attenuate OA pathology in mice.

Conclusion: Mitiglinide, identified via FDA-drug-library screening, alleviates OA progression by suppressing NLRP3 inflammasome activation and ECM degradation via activation of the Nrf2/HO-1 signaling pathway. This positions mitiglinide as a repurposed disease-modifying OA drug candidate.

Keywords

Mitiglinide; NLRP3 Inflammasome; Nrf2/HO-1 Pathway; Osteoarthritis; Pyroptosis.

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