Epigenetic remodeling and apoptotic activation by Chidamide suppress small cell lung cancer in molecularly distinct subtypes

Small cell lung cancer (SCLC), known for its aggressive nature and resistance to treatment, continues to evade effective targeted therapies. This study investigates the therapeutic potential of Chidamide, a subtype-selective histone deacetylase inhibitor (HDACi), in molecularly distinct SCLC models. In vitro, Chidamide showed dose- and time-dependent cytotoxicity across SCLC-A/N/P subtypes (H69, H526, H446), inhibiting proliferation (IC50: 1.979–4.9 μM) and clonogenicity (P < 0.001). It also caused G1/S arrest by increasing p21/p27 levels and decreasing Cyclin E1/CDK2 expression. Mechanistically, Chidamide elevated overall histone H3/H4 acetylation by inhibiting HDAC1/2/3, triggered γ-H2AX-associated DNA damage, and activated mitochondrial apoptosis. Flow cytometry confirmed dose-dependent apoptosis induction (12.45–43.03% across cell lines) and G1-phase accumulation (up to 61.8% in H69). In vivo, oral Chidamide (12.5–25 mg/kg) significantly inhibited xenograft tumor growth, aligning with increased histone acetylation, p21 expression, and Cleaved caspase-3 in treated tumors. Collectively, these results position Chidamide as a promising epigenetic candidate for SCLC therapy, demonstrating preclinical efficacy across molecular subtypes through modulation of chromatin architecture and DNA damage response.