Emerging Dual Roles of ALKBH5 in Ischemia-reperfusion Injury: Mechanisms and Therapeutic Implications.

Ischemia-reperfusion injury (IRI) is a critical pathological process affecting multiple organs, including the heart, brain, kidney, and liver. Recent studies have highlighted the dual roles of AlkB homolog 5 (ALKBH5), an N6-methyladenosine (m⁶A) RNA demethylase, in regulating cellular responses to IRI through epigenetic mechanisms. This review synthesizes current evidence on ALKBH5 involvement in metabolic reprogramming, autophagy, apoptosis, pyroptosis, and inflammation across organ-specific IRI models. We establish a unifying framework in which ALKBH5 functions as a double-edged sword, exerting either protective effects (such as sirtuin 1 (SIRT1) activation in the heart) or detrimental outcomes (such as tricarboxylic acid (TCA) cycle suppression), depending on tissue-specific microenvironments, disease stage dynamics, and downstream effector crosstalk (e.g., TCA cycle, SIRT1, PANoptosis). Despite its therapeutic potential, challenges in translation persist due to ALKBH5’s bidirectional effects and the lack of tissue-specific delivery systems. Future research should aim to resolve these controversies through advanced techniques such as single-cell m⁶A epitranscriptomics and develop spatiotemporally targeted modulators for precise intervention.