Lipid-autophagy crosstalk in glioblastoma: A context-dependent stress-adaptation interface under temozolomide pressure.

Abstract

Glioblastoma (GB) is characterized by aggressive progression and frequent recurrence despite temozolomide (TMZ)-based therapy. Although resistance is commonly linked to DNA repair mechanisms, these pathways do not fully explain tumor persistence under therapeutic stress. Accumulating evidence suggests that metabolic reprogramming, particularly crosstalk between lipid metabolism and autophagy, may contribute to GB adaptation under TMZ-induced stress. We discuss how this lipid-autophagy interface may enable tumor cells to reconfigure energy production, maintain redox balance, and remodel membranes in response to therapy. Although the available evidence remains predominantly preclinical, convergent findings from lipidomic analyses and functional perturbation studies support lipid-autophagy crosstalk as an emerging contributor to TMZ resistance. This review presents this interaction as a testable conceptual framework for understanding metabolic adaptation to TMZ and discusses its potential therapeutic relevance.