Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin

作者：Jie Li, Yuhao Li, Xiaoyang Zhou, Shushu Yang, Dong Liu, Hao Wen, Xiaoling Chen, Chengjie Duan, Meiling Yu, Mengjun Zhang, Bo Tang, Yong Wang, Li Wang, Yuzhang Wu · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02486-3 · 被引用次数：16 · 研究领域：Ferroptosis and cancer prognosis、Adipokines, Inflammation, and Metabolic Diseases、Immune cells in cancer

Abstract Chronic inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8 + T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8 + T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation bet...