The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.

Sigmar1 is a multifunctional molecular chaperone protein located on the Mitochondria-associated endoplasmic reticulum membranes (MAM). Recent studies have shown that Sigmar1 is not only a regulatory protein involved in cellular stress responses but also plays a significant role in the process of autophagy. It regulates the initiation and progression of autophagy by influencing multiple autophagy-related signaling pathways and interacting with key proteins such as LC3 and GABARAP. This regulation exhibits a dual nature. On one hand, it can induce protective autophagy, helping cells cope with stress such as oxidative stress and endoplasmic reticulum stress, thereby playing a protective role in the progression of diseases such as neurodegenerative disorders and cardiovascular diseases. On the other hand, in certain cancers, Sigmar1 may also promote tumor cell survival through autophagy regulation, thereby exacerbating disease progression. Consequently, developing agonists and antagonists targeting Sigmar1 has become a highly promising therapeutic strategy. This review provides a systematic overview of recent advances in the biological characterization of Sigmar1 and its molecular mechanisms in regulating autophagy. It summarizes the multifaceted roles of Sigmar1 in various diseases and discusses current research progress and the application prospects of Sigmar1 agonists and antagonists, aiming to establish a theoretical foundation for the development of novel Sigmar1-based therapeutic strategies for human diseases.