Bidirectional crosstalk between ER stress and lipid metabolism: From proteostasis to tumor adaptation

Abstract Endoplasmic reticulum (ER) stress is a central adaptive response that maintains proteostasis under diverse metabolic and environmental challenges. In cancer, ER stress and lipid metabolism form a tightly coupled, bidirectional regulatory network that integrates protein quality control with lipid remodeling. Through the unfolded protein response (UPR), ER stress reprograms lipid synthesis, oxidation, and storage to sustain energy balance and membrane integrity. Conversely, dysregulated lipid accumulation disrupts ER homeostasis and amplifies stress signaling, creating a feedback loop between metabolic and proteostatic imbalance. Proteostasis systems, including the ubiquitin-proteasome system (UPS) and autophagy, cooperate with UPR signaling to fine-tune this adaptive balance and enhance tumor survival under stress. This review highlights the bidirectional crosstalk between ER stress and lipid metabolism from the perspective of proteostasis-driven tumor adaptation and summarizes emerging therapeutic strategies such as small-molecule modulators, natural products, and combination therapies that target this adaptive network to overcome drug resistance and improve cancer treatment.