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  3. A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response

A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response

  • Mol Cell. 2025 Sep 4;85(17):3225-3240.e10. doi: 10.1016/j.molcel.2025.08.009.
Jinhua Li 1,  Yansong Zhang 2,  Jingyu Peng 1,  Wei Yang 3,  Yanzhe Pan 1,  Ying Xu 1,  Jiayi Yao 1,  Siyuan Lin 1,  Yizhi Li 1,  Xinran Gu 1,  Wei Dong 1,  Xiang Yu 4,  Ming Ge 5,  Min Liu 6,  Alan Jian Zhu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China.
  • 2 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China.
  • 3 Department of Neurosurgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
  • 4 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking University McGovern Institute, Peking University, Beijing 100871, China.
  • 5 Department of Neurosurgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. Electronic address: geming@mail.ccmu.edu.cn.
  • 6 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: liumin02@pku.edu.cn.
  • 7 State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu, Sichuan 610213, China. Electronic address: zhua@pku.edu.cn.
PMID: 40865521 DOI: 10.1016/j.molcel.2025.08.009
Abstract

Recent studies highlight the antioxidant role of lipid droplets (LDs) in shielding unsaturated lipids from peroxidation. While LDs accumulate during oxidative stress, the underlying mechanism remains unclear. Our previous research revealed that intracellular Amino acids directly bind to and activate the E3 ubiquitin Ligase Ubr1 to degrade Plin2, an LD protein inhibiting lipolysis. Here, we unexpectedly find that Ubr1's ability to bind to Amino acids is inhibited during oxidative stress. Mechanistically, oxidative stress-induced lipid peroxidation blocks the activity of Hsc70-4, an ATPase that maintains the amino-acid-binding ability of Ubr1. 4-hydroxynonenal, a reactive product of lipid peroxidation, covalently modifies and inactivates Hsc70-4, leading to Ubr1 inactivation, Plin2 stabilization, and LD accumulation. Increased LDs minimize lipid peroxidation, thus protecting cells from oxidative damage and cell death. Together, we identify a regulator of amino acid sensing with redox-dependent activity, bridging the gap in understanding how lipid peroxidation stimulates LD-dependent antioxidant responses.

Keywords

4-hydroxynonenal; HSPA8; Hsc70-4; Plin2; Ubr1; amino acid sensing; antioxidant response; lipid droplet; lipid peroxidation.

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