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 and Xunde Xian ()
Additional contact information
Pingping Lai: Peking University
Guolin Miao: Peking University
Yinqi Zhao: Peking University
Yufei Han: Peking University
Yanwei Li: China Medical University
Yiran Liu: Peking University
Jiabao Guo: Peking University
Wenxi Zhang: Peking University
Xin Guo: Peking University Third Hospital
Yitong Xu: Peking University
Lianxin Zhang: Peking University
Gonglie Chen: Peking University
Zihao Zhou: Peking University
Si Mei: Peking University
Jingxuan Chen: Peking University
Jinxuan Chen: Peking University
Luzheng Xu: Peking University
Chong Zhang: China Medical University
Yang Ding: China Medical University
Xiaoguang Dou: China Medical University
Shengmei Wen: NGGT (Suzhou) Biotechnology Co. Ltd
Sin Man Lam: Chinese Academy of Sciences
Guanghou Shui: Chinese Academy of Sciences
Yuhui Wang: Peking University
Wei Huang: Peking University
Dongyu Zhao: Peking University
Xunde Xian: Peking University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57585-0

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