Abstract
Selective autophagy, which is the targeted degradation of specific cellular components through lysosomes, serves a complex role in hepatocellular carcinoma (HCC). The present review explores the following 10 distinct selective autophagy pathways in HCC: Mitophagy, lysophagy, reticulophagy, pexophagy, nucleophagy, ribophagy, lipophagy, glycophagy, ferritinophagy and fluidophagy. In HCC, mitophagy can support therapy resistance by clearing damaged mitochondria, whereas lysophagy maintains lysosomal homeostasis through receptor recycling, such as coiled-coil domain containing 50. Reticulophagy, mediated by family with sequence similarity 134 member B (FAM134B), protects HCC cells from ferroptosis during kinase inhibitor treatment. Ferritinophagy, driven by nuclear receptor coactivator 4, regulates iron availability and sensitivity to ferroptotic cell death. Lipophagy has dual functions, where it provides energy substrates for tumor survival whilst potentially suppressing tumor growth through BCL2-interacting protein 3-mediated mechanism in fatty livers. Altogether, these aforementioned pathways offer therapeutic opportunities through inhibition, activation or synthetic lethality approaches. Promising strategies include combining ferroptosis inducers with autophagy inhibitors, targeting specific receptors, (such as FAM134B) and modulating mitophagy regulators (such as dynamin-related protein 1). In addition, autophagy-related biomarkers (sequestosome 1, LC-3B and beclin-1) are associated with clinical outcomes and may guide patient stratification. Given the bidirectional nature of selective autophagy in HCC, personalized approaches based on tumor context, specific pathway dependencies and disease stage are essential for effective therapeutic intervention.