SETDB1 enhances starvation-induced lipophagy by inhibiting m6A-mediated mRNA decay via DDX5 methylation

  • Autophagy. 2026 May 17:1-23. doi: 10.1080/15548627.2026.2669984.
Wenjun Wang  1  2 ,  Yanhong Wang  2 ,  Lige Hou  2 ,  Xiaoyun Wei  2 ,  Wenqi Guo  2 ,  Juan Huang  2 ,  Junyang Tan  2  3 ,  Qiuxia Lu  4 ,  Qi Zhao  4 ,  Zhenyu Ju  2  3 ,  Jianshuang Li  1  2  5 ,  Qinghua Zhou  2  6
Affiliations
  • 1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China.
  • 2. The College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
  • 3. The First Affiliated Hospital, Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong, China.
  • 4. College of Food and Biological Engineering, Chengdu University, Chengdu, Sichuan, China.
  • 5. Department of Orthopaedics, Guangzhou Red Cross Hospital, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China.
  • 6. Shantou Clinical Medical College of Jinan University (Shantou Central Hospital), Jinan University, Shantou, Guangdong, China.
PMID: 42087801 DOI: 10.1080/15548627.2026.2669984
Abstract

Lipophagy, a selective form of macroautophagy/Autophagy, degrades lipid droplets (LDs) to provide energy and is implicated in metabolic disorders. The molecular mechanism underlying lipophagy induction remains incompletely understood. This study explored the role of SETDB1 in starvation-induced Autophagy and lipophagy. We demonstrate that SETDB1 deficiency exacerbates starvation-induced hepatic lipid accumulation by inhibiting lipophagy. Mechanistically, starvation promotes ATM-mediated phosphorylation of SETDB1, which enhances its interaction with and methylation of the RNA helicase DDX5. In SETDB1-knockout hepatocytes, hypomethylation of DDX5 facilitates the formation of the DDX5-METTL3-METTL14 complex, increasing m6A modification of BECN1 and TFEB mRNAs. This modification promoted YTHDF2-mediated decay of these transcripts, thereby inhibiting starvation-induced Autophagy and lipophagy. Furthermore, administration of the SETDB1 activator (R, R)-59 significantly enhances lipophagy and attenuates starvation-induced hepatic steatosis. Collectively, our findings reveal a novel pathway in which SETDB1 deficiency drives m6A-mediated mRNA degradation to suppress lipophagy, thereby contributing to hepatic steatosis.Abbreviations: AA free: amino acid deprivation; ATG14: Autophagy related 14; ATG5: Autophagy related 5; ATG7: Autophagy related 7; ATM: ATM serine/threonine kinase; Baf A1: bafilomycin A1; DDX5: DEAD-box helicase 5; FASN: fatty acid synthase; LAMP1: lysosome associated membrane protein 1; LAMP2A: lysosome associated membrane protein 2A; LIPE/HSL: Lipase E, hormone sensitive type; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; METTL3: methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; METTL14: methyltransferase 14, N6-adenosine-methyltransferase non-catalytic subunit; MGLL/MGL: monoglyceride lipase; OA: oleic acid; OSBPL8/ORP8: oxysterol binding protein like 8; PLIN2: perilipin 2; PNPLA2/ATGL: patatin like domain 2, triacylglycerol lipase; SETDB1: SET domain bifurcated histone lysine methyltransferase 1; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like Autophagy activating kinase 1; YTHDF2: YTH N6-methyladenosine RNA binding protein F2.

Keywords
Autophagy; SETDB1; hepatic steatosis; lipophagy; m6A modification.
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