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September 19, 2025Open Access

ALDH2 in autophagy and cell death: molecular mechanisms and implications for diseases

YDYu DuanZhejiang Sci-Tech University ZSZhiying ShanMichigan Technological University JPJiaojiao PangShandong University

Key Points

ALDH2 regulates crucial pathways of cell death, including apoptosis, necroptosis, and ferroptosis, influencing disease outcomes.
The ALDH2rs671 mutation, affecting millions, increases susceptibility to various diseases linked to impaired autophagic function.
Current research showcases ALDH2's dual role in detoxifying harmful aldehydes and modulating cellular mechanisms like autophagy.
Understanding ALDH2's regulatory mechanisms may open avenues for innovative therapeutic strategies in human diseases.

Abstract

Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme, is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes. The ALDH2rs671 mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases. In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes, ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis). This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death. In addition, we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases, aiming to provide a novel theoretical framework for human disease treatment.

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