H4K8 lactylation-mediated ferroptosis defense drives EGFR-TKI resistance in lung adenocarcinoma

Abstract

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major clinical challenge in non-small cell lung cancer. Emerging evidence indicates that metabolic reprogramming and epigenetic alterations contribute to drug resistance, particularly through the evasion of ferroptosis, a regulated form of cell death characterised by lipid peroxidation. This study investigated the role of lactate-associated histone modifications in driving EGFR-TKI resistance. Resistant lung adenocarcinoma tissues and cell lines were analysed using transcriptomics, Cleavage Under Targets and Tagmentation (CUT&Tag) profiling, and biochemical assays. Glycolytic activity, lactate accumulation, and ferroptosis-related lipid peroxidation were assessed, followed by genetic and pharmacological interventions and in vivo xenograft validation. Resistant cells exhibited enhanced glycolysis and lactate accumulation, with pathway analyses highlighting ferroptosis evasion as a key resistance-associated process. Consequently, histone H4 lysine 8 lactylation (H4K8la) was significantly elevated in resistant tissues and cells. Mechanistically, H4K8la was enriched at transcription start sites, particularly at the promoter of aldo-keto reductase family 1 member C1 (AKR1C1). This epigenetic modification profoundly suppressed ferroptosis and promoted drug resistance. Disrupting this H4K8la-AKR1C1 defence axis restored lipid peroxidation, increased ferroptotic sensitivity, and resensitised resistant cells to EGFR-TKIs, as confirmed in vivo. These findings reveal a novel lactate-driven epigenetic mechanism that orchestrates ferroptosis escape and EGFR-TKI resistance, offering a promising therapeutic strategy to overcome treatment failure.