Hippo pathway in cancer ferroptosis: from mechanism insights to targeted therapies

Abstract

Ferroptosis is an iron-dependent form of regulated cell death driven by membrane lipid peroxidation and has become an important therapeutic vulnerability in cancer. The Hippo pathway, through its transcriptional effectors Yes-associated protein and transcriptional coactivator with PDZ-binding motif, links cell contact, mechanical stress, metabolism and tissue organization to cancer-cell state. Recent studies show that Hippo activity can either sensitize or protect tumor cells from ferroptosis, depending on the tissue microenvironment, effector-driven signaling and treatment pressure. This review integrates the molecular mechanisms of Hippo signaling and ferroptosis, then summarizes the evidence across four mechanistic layers: cell-contact and mechanotransduction inputs, direct control of ferroptosis machinery, metabolic and redox integration, and epigenetic or non-coding regulation. We further examine how this axis shapes cancer progression, stem-like states, drug resistance, tumor–stroma communication and immune therapy. Therapeutic strategies include direct disruption of YAP/TAZ–TEAD activity, pharmacological induction of ferroptosis, metabolic co-targeting, natural-product combinations, oncolytic viruses, engineered extracellular vesicles and nanomedicine. The major translational need is to define when Hippo activation marks ferroptosis vulnerability and when it marks ferroptosis resistance. Patient stratification, spatially resolved models, dynamic pharmacodynamic biomarkers and clinically realistic combination studies will be essential for translating these microenvironment-specific signaling cascades into a precision treatment strategy.