2. Academic Validation
  3. Lactucopicrin promotes the autophagic degradation of MAP2K4/MKK4 by mediating CCDC50 palmitoylation to alleviate osteoarthritis progression

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

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.

Figures
Products