Marine Natural Products with Novel Mechanisms of Action: From Disrupting Gene Expression to Reshaping the Tumor Microenvironment and Beyond

Drug resistance and undruggable targets persist as major therapeutic hurdles. Marine natural products (MNPs), which have evolved under extreme conditions, offer structurally diverse scaffolds that engage targets via unconventional mechanisms. This review systematically groups MNPs by their precise molecular targets and modes of action, moving beyond cytotoxicity tabulation. We cover agents that disrupt gene expression-spliceosome inhibitors (FR901464, thailanstatin A), translation initiation blockers (pateamine A, hippuristanol), and elongation arrest compounds (plitidepsin, psymberin), as well as those inducing genomic damage through topoisomerase poisoning or DNA alkylation. Beyond oncology, we critically assess MNPs modulating proteostasis (marizomib, carmaphycins), targeting undruggable protein–protein interfaces (siladenoserinol A, marinopyrrole A), reshaping epigenetics (largazole, psammaplin A), and triggering non-apoptotic death pathways (ferroptosis, cuproptosis, pyroptosis). We discuss structure–function correlations and translational bottlenecks for representative clinical-stage candidates, and discuss how cryo-EM, AI-driven prediction, and synthetic biology are converting these exotic scaffolds into viable leads. By linking mechanistic depth with translational roadmaps, this review aims to inspire both academic and industrial researchers to harness marine molecular diversity for next-generation precision medicines.