N-Methyladenosine (mA), the most prevalent internal modification in eukaryotic messenger RNA (mRNA), plays crucial, context-dependent (e.g., tumor type, stage, or microenvironmental conditions like hypoxia) roles in cancers. Its dynamics are governed in part by the "eraser" protein alkB homolog 5 (ALKBH5), an Fe/α-ketoglutarate-dependent dioxygenase that removes mA marks to regulate mRNA stability and translation. ALKBH5 activity is intricately modulated by its structural domains double-stranded β-helical (DSBH) and post-translational modifications (such as Small Ubiquitin-like Modifier modification (SUMOylation) and phosphorylation). Furthermore, it is regulated through interactions with RNA-binding proteins and non-coding RNAs (such as microRNAs(miRNAs) and circular RNAs(circRNAs)), as well as microenvironmental cues (such as hypoxia and oxidative stress). Crucially, ALKBH5 exerts the dualistic control over autophagy, a conserved lysosomal degradation pathway critical for cellular homeostasis, which paradoxically suppresses early tumorigenesis yet promotes progression and therapy resistance in established cancers. This review aims to synthesize recent paradigm-shifting advances elucidating the complex interplay between ALKBH5-mediated epitranscriptomic regulation and autophagy in cancers. We comprehensively examine the molecular structure and multifaceted regulatory networks of ALKBH5, delve into the core mechanisms linking ALKBH5 to autophagy machinery (such as. ALKBH5/epidermal growth factor receptor (EGFR)-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR), ALKBH5/B-cell lymphoma-2 (BCL-2)/Beclin1, ALKBH5/ATP-binding cassette transporter A1 (ABCA1), ALKBH5/fatty acid binding protein 5 (FABP5)/fatty acid synthase (FASN), ALKBH5/tetraspanin 1 (TSPAN1), ALKBH5/yin yang 1 (YY1)/Autophagy-related protein 4B (ATG4B) pathways), explicitly highlighting their opposing impacts in specific malignancies: for instance, autophagy suppression driving progression in ovarian cancer (ALKBH5/EGFR-PI3K-AKT-mTOR, ALKBH5/BCL-2/Beclin1) versus autophagy activation exerting tumor-suppressive effects in colorectal cancer (ALKBH5/FABP5/FASN) and gastric cancer (ALKBH5/YY1/ATG4B). Finally, we discuss the therapeutic implications of targeting the ALKBH5-autophagy axis, identify unresolved mechanistic questions and knowledge gaps, and outline future research directions for leveraging this pathway in precision cancer therapy. 6 6 2+ 6
