Decoding the crosstalk between ubiquitination and acylation in cancer drug resistance: from mechanisms to targeted strategies

This review systematically summarizes the interplay between ubiquitination and various acylation modifications, such as lactylation, acetylation, succinylation, and palmitoylation, in cancer drug resistance. The article highlights how these post-translational modifications dynamically regulate the stability, activity, and localization of key proteins through competitive, synergistic, or cascading mechanisms. These interactions influence DNA damage repair, cell death (e.g., ferroptosis and apoptosis), signaling pathway reprogramming, and tumor microenvironment remodeling, thereby mediating resistance to chemotherapy, targeted therapy, and immunotherapy. Targeted strategies against this network, including p300/CBP inhibitors and PROTAC degraders, show promise in reversing resistance, yet clinical translation faces challenges such as selectivity, delivery efficiency, and mechanistic complexity. Integrated multi-omics and combination therapies represent future directions.