2. Academic Validation
  3. Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD

Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD

  • Nat Commun. 2025 Dec 12;16(1):11092. doi: 10.1038/s41467-025-65982-8.
Mengjie Li # 1 2,  Qian Ou # 1,  Qiang Qin # 1,  Jiaxi Chen 1,  Sen Yang 3,  Jie Zhao 4,  Hua Meng 5,  Xu Li 6,  Pinglong Xu 3,  Cunqi Ye 3,  Xiaojian Wang 7
Affiliations

Affiliations

  • 1 Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • 3 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 4 Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 5 Department of General Surgery, China-Japan Friendship Hospital, Beijing, China.
  • 6 Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, China.
  • 7 Institute of Immunology and Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41387436 DOI: 10.1038/s41467-025-65982-8
Abstract

High-fat diet (HFD) is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular pathways that connect dietary fats to liver dysfunction remain unclear. Here, we discover that hepatic downregulation of Raf kinase inhibitory protein (RKIP) in MASLD patients and male mice is linked to fatty acid uptake, which causes endoplasmic reticulum (ER)-associated degradation of RKIP by inhibiting its S-palmitoylation. Via facilitating the m6A-modified RNA binding of YTHDF1, RKIP is required for the efficient translation of PEMT, an essential enzyme in maintaining phosphatidylcholine (PC) / phosphatidylethanolamine (PE) ratio and ER homeostasis. Hepatocyte-specific RKIP depletion in male mice exacerbates the PC/PE imbalance and ER stress, resulting in lipid droplets accumulation and MASLD progression. Notably, RKIP correlates positively with PEMT protein but inversely with MASLD development. These findings uncover a cellular mechanism of HFD-RKIP-PEMT that underlies diet-induced liver Metabolic Disease and propose RKIP as a target for MASLD prevention.

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