Ferroptosis as a Translational Axis in Small Cell Lung Cancer: A Systematic Review of Redox Pathways and Precision Oncology Prospects

An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC.

This systematic review, registered in PROSPERO (CRD420251090058), followed PRISMA 2020 guidelines. Comprehensive research of PubMed, Scopus, and Web of Science was performed for studies published between January 2010 and July 2025 investigating ferroptosis mechanisms, genetic or pharmacological modulation, or molecular profiling in SCLC. Two reviewers independently performed data extraction and quality assessment.

Nineteen preclinical studies met the inclusion criteria. Key regulators included solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthetase long chain family member 4 (ACSL4). The molecular subtypes of SCLC, achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and Yes1 associated transcriptional regulator (YAP1) exhibit differential ferroptosis gene expressions, influencing therapeutic responsiveness. Non-neuroendocrine subtypes are more ferroptosis-prone, whereas neuroendocrine variants display enhanced antioxidant defenses. Ferroptosis induction also promotes immune activation through stimulator of interferon genes (STING)-mediated CD8⁺ T-cell recruitment.

Ferroptosis constitutes a promising therapeutic axis in SCLC. Integrating ferroptosis biomarkers into molecular stratification frameworks could refine patient selection and support precision oncology strategies, warranting further translational and clinical validation.