Lactucopicrin promotes the autophagic degradation of MAP2K4/MKK4 by mediating CCDC50 palmitoylation to alleviate osteoarthritis progression

  • Autophagy. 2026 Mar;22(3):526-544. doi: 10.1080/15548627.2025.2601041.
Wenjun Li  1  2 ,  Qijie Sun  1  3 ,  Konghe Hu  2 ,  Dongmei Tang  2 ,  Cheng Yang  4 ,  Yingchao Xie  5 ,  Xiaodong Peng  2 ,  Yongtao Deng  2 ,  Jiansen Lu  6 ,  Yong Qi  1 ,  Yifen Lin  1 ,  Hongtao Sun  1 ,  Qinyu Tian  7 ,  Changpeng Xu  1 ,  Xinggui Tian  8  9  10 ,  Huaji Jiang  2
Affiliations
  • 1. Department of Orthopedics, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
  • 2. Department of Orthopaedics, The State Key Clinical Specialty in Orthopaedics, Yuebei People's Hospital, Affiliated to Shantou University Medical College, Shaoguan, China.
  • 3. Department of Orthopedics, Xinzhou People's Hospital, Xinzhou, China.
  • 4. Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 5. Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 6. Department of Joint Surgery, Shaoguan First People's Hospital, Southern Medical University, Shaoguan, China.
  • 7. Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 8. University Center of Orthopaedic, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany.
  • 9. Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany.
  • 10. Center for Orthopaedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald, Germany.
PMID: 41566717 DOI: 10.1080/15548627.2025.2601041
Abstract

Macroautophagy/Autophagy plays a crucial role in maintaining cellular homeostasis and protecting against osteoarthritis (OA). Its dysregulation contributes to OA progression by promoting chondrocyte senescence, inflammation, and cartilage degradation. Enhancing autophagic activity thus represents a promising therapeutic strategy for OA. In this study, we identified lactucopicrin (LCP) as an effective Autophagy activator that alleviates OA progression in a mouse model induced by the destabilization of the medial meniscus, by reducing cartilage degeneration and preserving matrix integrity. Mechanistically, LCP enhances ZDHHC4-catalyzed palmitoylation of the cargo receptor CCDC50, facilitating the selective autophagic degradation of MAP2K4/MKK4, leading to the suppression of MAPK/JNK signaling and the attenuation of chondrocyte senescence. Structural analysis reveals that LCP directly binds to His72 of ZDHHC4 via its p-hydroxybenzoic acid moiety, boosting enzymatic activity and promoting selective Autophagy. These findings establish a novel ZDHHC4-CCDC50-MAP2K4/MKK4-MAPK/JNK regulatory axis linking palmitoylation, Autophagy, and senescence, and identify LCP as a promising agent for targeting this pathway to inhibit OA progression. Furthermore, this study provides mechanistic insights into the crosstalk between Autophagy, protein palmitoylation, and cellular senescence in degenerative joint disease.Abbreviation: ABE: acyl-biotin exchange; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5; CCDC50: coiled-coil domain containing 50; COL2A1: Collagen, type II, alpha 1; COL10A1: Collagen, type X, alpha 1; DARTS: drug affinity responsive target stability; DHHC: Asp-His-His-Cys catalytic motif; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; H2O2: hydrogen peroxide; LCP: lactucopicrin; IL6: interleukin 6; MAPK/JNK: mitogen-activated protein kinase; MAP2K4/MKK4: mitogen-activated protein kinase kinase 4; MMP13: matrix metallopeptidase 13; OA: osteoarthritis; p-MAPK/JNK: phosphorylated mitogen-activated protein kinase; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; ZDHHC: zinc finger, DHHC domain containing.

Keywords
Autophagy; CCDC50; MAP2K4/MKK4; chondrocyte senescence; osteoarthritis; palmitoylation.
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