Morin-mediated regulation of apoptosis-autophagy crosstalk in Cancer: molecular mechanisms, preclinical evidence, and translational challenges.

Morin (2',3,4',5,7-pentahydroxyflavone) is a polyphenolic dietary flavonoid found naturally in foods and has demonstrated anticancer effects in multiple preclinical models. This narrative review presents a comprehensive pharmacological analysis of morin's capacity to modulate apoptosis and autophagy, which are convergent pathways of programmed cell death (PCD) in both solid and hematological malignancies. Morin has been reported to influence intracellular reactive oxygen species (ROS) levels and disrupt the mitochondrial membrane potential (ΔΨm), thereby affecting the AMPK-mTOR-ULK1-Beclin-1 autophagic pathway. This review synthesizes preclinical data obtained from in vitro cancer cell line models, in vivo xenograft and chemical-induced tumor systems, and hypothesis-generating in silico molecular docking and network pharmacology studies. The significant crosstalk between apoptosis and autophagy appears to involve the Bcl-2/Beclin-1 pathway, cleavage of autophagy-related proteins by caspases, and shared redox stress. Mechanistic interpretation should be used with caution, as several studies have used associative molecular end points, and the accumulation of LC3-II does not equate to complete autophagic flux. Novel nanoformulation-based drug delivery strategies, the potential of chemo-sensitization in drug-resistant tumor models, and available preclinical safety and toxicology data are examined in the context of the pharmacokinetic limitations of morin, such as poor oral bioavailability, low aqueous solubility, intestinal metabolism, P-glycoprotein efflux, and limited clinical pharmacokinetic validation. Pharmacological studies suggest that morin may be classified as a multi-target phytopharmacological agent. However, more rigorous studies are required for target validation, including autophagy flux assays, clinically relevant tumor models, and pharmacokinetic optimization, before it can be translated into a therapeutic application.