Discovery of a Novel HDAC1 Inhibitor to Potentiate Ferroptosis with Arachidonic Acid in ESCC

Ferroptosis represents a promising therapeutic strategy for esophageal squamous cell carcinoma (ESCC), but its efficacy is often limited by intrinsic metabolic defenses. Herein, arachidonic acid (AA) acts as a potent sensitizer for class I histone deacetylase (HDAC) inhibitor-induced ferroptosis. Guided by the binding mode of the lead compound with HDAC1, we developed a library of HDAC inhibitors, from which L17h was identified as a novel and highly selective HDAC1 inhibitor. Mechanistically, L17h-mediated HDAC1 inhibition transcriptionally upregulated acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, which primed cells to metabolize supplemental AA and drove massive lipid peroxidation (LPO), leading to profound sensitization to ferroptosis. Crucially, this epigenetically primed ferroptosis elicited robust immunogenic cell death (ICD), promoting dendritic cell (DC) maturation and intratumoral T cell infiltration for systemic antitumor immunity. This work unveils crosstalk between epigenetics and fatty acid metabolism, proposing a combinatorial targeted strategy for ferroptosis-based immunotherapy in ESCC.