SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation

Pingping Lai; Guolin Miao; Yinqi Zhao; Yufei Han; Yanwei Li; Yiran Liu; Jiabao Guo; Wenxi Zhang; Xin Guo; Yitong Xu; Lianxin Zhang; Gonglie Chen; Zihao Zhou; Si Mei; Jingxuan Chen; Jinxuan Chen; Luzheng Xu; Chong Zhang; Yang Ding; Xiaoguang Dou; Shengmei Wen; Sin Man Lam; Guanghou Shui; Yuhui Wang; Wei Huang; Dongyu Zhao; Xunde Xian

doi:10.1038/s41467-025-57585-0

SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation

Nat Commun. 2025 Mar 11;16(1):2430. doi: 10.1038/s41467-025-57585-0.

Authors

Pingping Lai^#¹, Guolin Miao^#^{1

2}, Yinqi Zhao^#¹, Yufei Han^#¹, Yanwei Li³, Yiran Liu⁴, Jiabao Guo¹, Wenxi Zhang¹, Xin Guo², Yitong Xu¹, Lianxin Zhang¹, Gonglie Chen¹, Zihao Zhou¹, Si Mei¹, Jingxuan Chen¹, Jinxuan Chen¹, Luzheng Xu⁵, Chong Zhang³, Yang Ding³, Xiaoguang Dou³, Shengmei Wen⁶, Sin Man Lam^{7

8}, Guanghou Shui⁷, Yuhui Wang¹, Wei Huang¹, Dongyu Zhao⁴, Xunde Xian^{9

10}

Affiliations

¹ Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China.
² Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
³ Department of Infectious Diseases, Shengjing Hospital, China Medical University, Shenyang, China.
⁴ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China.
⁵ Peking University Medical and Health Analysis Center, Peking University, Beijing, China.
⁶ NGGT (Suzhou) Biotechnology Co. Ltd, Suzhou, China.
⁷ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
⁸ Lipidall Technologies Company Limited, Changzhou, 213022, Jiangsu Province, China.
⁹ Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China. xianxunde@bjmu.edu.cn.
¹⁰ Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China. xianxunde@bjmu.edu.cn.

^# Contributed equally.

Abstract

Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.

MeSH terms

Animals
Cricetinae
Diet, High-Fat / adverse effects
Disease Models, Animal
Fatty Liver / genetics
Fatty Liver / metabolism
Fatty Liver / prevention & control
Humans
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Obese
PTEN Phosphohydrolase* / genetics
PTEN Phosphohydrolase* / metabolism
Proteolysis / drug effects
Proto-Oncogene Proteins c-akt* / metabolism
Ubiquitination*
X-Linked Inhibitor of Apoptosis Protein* / genetics
X-Linked Inhibitor of Apoptosis Protein* / metabolism

Substances

PTEN Phosphohydrolase
X-Linked Inhibitor of Apoptosis Protein
Proto-Oncogene Proteins c-akt
PTEN protein, human
XIAP protein, human

Abstract

MeSH terms

Substances

Grants and funding