Advances in hydroxamic acid hybrids for liver cancer therapy: a decade of progress (2016–2025)

Liver cancer, which originates from hepatocytes, ranks among the most commonly diagnosed cancers and stands as a leading cause of cancer-related deaths, primarily due to late diagnosis and its rapid progression. Liver cancer, especially metastatic liver tumors, often relies on chemotherapy. Still, drug resistance driven by the overexpression of efflux pumps, reduced systemic drug exposure due to hepatic metabolism, low efficacy, and high toxicity creates an urgent need to explore novel chemotherapeutic agents. Hydroxamic acid serves as the zinc-binding group (ZBG) in most histone deacetylase (HDAC) inhibitors and is an important anti-liver cancer pharmacophore. Hydroxamic acid hybrids harness the epigenetic potency of hydroxamic acid through modular pharmacophore integration, providing multitarget efficacy, resistance overcoming, and therapeutic versatility, and thus represent promising candidates for next-generation liver cancer therapies.