Research progress on the role of palmitoyl acyl transferases in tumors and their inhibitors

[Background] Palmitoylation is a prevalent form of post-translational modification in proteins.It includes S-palmitoylation, N-palmitoylation and O-palmitoylation, among which S-palmitoylation is a reversible modification and is the most extensively studied and frequently observed.Palmitoyl acyl transferases(PAT), a family of integral membrane enzymes known as DHHC(Asp-His-His-Cys), are responsible for catalyzing post-translational palmitoylation of substrate proteins, which contain a consensus signature DHHC domain.The human DHHC family comprises 23 members, which exhibit distinct functions in various tissues and cellular contexts.Substantial evidence has linked DHHC family to the oncogenesis and progression of multiple cancers, including breast, lung and colorectal cancers, where they influence tumor cell biology by regulating palmitoylation levels of key signaling pathways or oncogenes.Since the initial report of the DHHC family in 1979, research progressed relatively slowly until the crystal structure of DHHC20 was successfully elucidated in 2018.This breakthrough not only elucidated the molecular mechanisms of palmitoylation catalyzed by the DHHC domain, such as substrate recognition and the specific pathway of palmitoyl group transfer, but also laid the structural foundation for in-depth understanding of the roles of DHHC family members in diseases.Crucially, it identified critical molecular targets for structure-based anticancer drug development against DHHC enzymes, thereby propelling subsequent research toward three frontiers:resolving additional family member structures, exploring their dynamic regulatory mechanisms within tumor microenvironments, and designing isoform-specific inhibitors.[Progress] Recent studies of DHHC have demonstrated that their dysregulation is associated with tumorigenesis, establishing their inhibitors as compelling targets for anticancer therapeutics.This review first delineates the mechanistic basis of DHHC-mediated post-translational modifications and their consequent dysregulation of cellular physiology, promoting cancer cell proliferation, survival, and immune evasion.It then characterizes oncogenic pathways modulated by DHHC across malignancies, including their context-dependent regulatory mechanisms.Structure-driven development of novel inhibitors represents an emerging strategic focus in contemporary drug discovery.For instance, the small-molecule compound PF-670462 promotes DHHC8 degradation, thereby attenuating palmitoylation of glutathione peroxidase 4(GPX4)and enhancing ferroptosis sensitivity.Despite these breakthroughs, DHHC inhibitor research still faces challenges:the functional diversity of family members leads to inadequate inhibitor specificity, and the dynamic regulatory nature of palmitoylation requires drugs to possess sustained inhibitory capacity.Future studies are needed to further elucidate the structures and functions of additional DHHC family members, develop highly specific inhibitors, and explore combination therapy strategies to advance the translation of this field from bench to bedside.Finally, the review synthesizes contemporary advances in DHHC inhibitor development through three strategic paradigms:natural product discovery, drug repurposing, and structure-based drug design.[Perspective] Current research demonstrates that DHHC inhibitors significantly suppress cancer cell proliferation and induce apoptosis, underscoring their therapeutic promise.Inhibitor research has evolved from early non-specific palmitic acid analogs to structure-based precision design, though multi-dimensional breakthroughs are still needed.On one hand, in-depth characterization of each DHHC family member's structure and substrate specificity leveraging technologies like Cryo-EM is required to reveal dynamic palmitoylation regulatory mechanisms and develop highly selective inhibitors.On the other hand, given the spatiotemporal dynamics of palmitoylation in the tumor microenvironment, the design of long-acting inhibitors or exploration of PROTAC(proteolysis-targeting chimera)technologies for sustained DHHC protein regulation is imperative.Moreover, combination strategies represent a pivotal therapeutic frontier.For instance, integrating DHHC inhibitors with immune checkpoint blockade counters immune evasion to enhance anti-tumor immunity, while synergism with chemotherapy or targeted agents may overcome therapeutic resistance.Meanwhile, clinical translation research should be expedited, including identifying patient subgroups with optimal response through biomarker screening, optimizing pharmacokinetic properties, and facilitating the transition of DHHC-targeted therapies from basic research to clinical application.This review summarizes the mechanistic roles and research landscape of DHHC inhibitors in cancer-targeted therapy, analyzes existing challenges and future prospects, and aims to provide novel insights and strategies for cancer precision medicine.