# Ferroptosis as a Translational Axis in Small Cell Lung Cancer: A Systematic Review of Redox Pathways and Precision Oncology Prospects **Authors:** Donatella Coradduzza, Anna La Salvia, Giuseppe Fanciulli, Maria Rosaria De Miglio PMC · DOI: 10.32604/or.2025.073045 · Oncology Research · 2026-03-23 ## TL;DR This review explores how ferroptosis, a type of cell death, could be a new treatment target in small cell lung cancer. ## Contribution The paper systematically reviews ferroptosis mechanisms and their therapeutic potential in SCLC molecular subtypes. ## Key findings - SLC7A11, GPX4, FSP1, and ACSL4 are key regulators of ferroptosis in SCLC. - Non-neuroendocrine SCLC subtypes are more susceptible to ferroptosis. - Ferroptosis can enhance immune responses via STING-mediated CD8+ T-cell recruitment. ## Abstract 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. ## Linked entities - **Genes:** SLC7A11 (solute carrier family 7 member 11) [NCBI Gene 23657], GPX4 (glutathione peroxidase 4) [NCBI Gene 2879], S100A4 (S100 calcium binding protein A4) [NCBI Gene 6275], ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182], ASCL1 (achaete-scute family bHLH transcription factor 1) [NCBI Gene 429], NEUROD1 (neuronal differentiation 1) [NCBI Gene 4760], POU2F3 (POU class 2 homeobox 3) [NCBI Gene 25833], YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413], STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] - **Diseases:** small cell lung cancer (MONDO:0008433), SCLC (MONDO:0008433) ## Full-text entities - **Genes:** alp (alopecia, recessive) [NCBI Gene 11691], KEAP1 (kelch like ECH associated protein 1) [NCBI Gene 9817] {aka INrf2, KLHL19}, HDAC6 (histone deacetylase 6) [NCBI Gene 10013] {aka CPBHM, HD6, JM21, KDAC6, PPP1R90}, NEUROD1 (neuronal differentiation 1) [NCBI Gene 4760] {aka BETA2, BHF-1, MODY6, NEUROD, T2D, bHLHa3}, ELOVL5 (ELOVL fatty acid elongase 5) [NCBI Gene 60481] {aka HELO1, SCA38, dJ483K16.1}, TOP1 (DNA topoisomerase I) [NCBI Gene 7150] {aka TOPI}, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) [NCBI Gene 5290] {aka CCM4, CLAPO, CLOVE, CWS5, HMH, MCAP}, MLKL (mixed lineage kinase domain like pseudokinase) [NCBI Gene 197259] {aka hMLKL}, PARP1 (poly(ADP-ribose) polymerase 1) [NCBI Gene 142] {aka ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1}, PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) [NCBI Gene 5210], Slc2a8 (solute carrier family 2, (facilitated glucose transporter), member 8) [NCBI Gene 56017] {aka D2Ertd44e, GLUT8, GlutX1}, Ptgs2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 19225] {aka COX2, Cox-2, PES-2, PGHS-2, PHS II, PHS-2}, RB1 (RB transcriptional corepressor 1) [NCBI Gene 5925] {aka OSRC, PPP1R130, RB, p105-Rb, p110-RB1, pRb}, Eno2 (enolase 2, gamma neuronal) [NCBI Gene 13807] {aka D6Ertd375e, Eno-2, NSE}, Parp1 (poly (ADP-ribose) polymerase family, member 1) [NCBI Gene 11545] {aka 5830444G22Rik, ARTD1, Adprp, Adprt1, PARP, PPOL}, Slc3a2 (solute carrier family 3 (activators of dibasic and neutral amino acid transport), member 2) [NCBI Gene 17254] {aka 4F2, 4F2HC, Cd98, Ly-10, Ly-m10, Ly10}, Pfkfb4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) [NCBI Gene 270198] {aka C230090D14}, SLC3A2 (solute carrier family 3 member 2) [NCBI Gene 6520] {aka 4F2, 4F2HC, 4T2HC, CD98, CD98HC, MDU1}, REST (RE1 silencing transcription factor) [NCBI Gene 5978] {aka DFNA27, GINGF5, HGF5, NRSF, WT6, XBR}, SPATA2 (spermatogenesis associated 2) [NCBI Gene 9825] {aka PD1, PPP1R145, tamo}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, Fgf21 (fibroblast growth factor 21) [NCBI Gene 56636] {aka Fgf8c}, ATL1 (atlastin GTPase 1) [NCBI Gene 51062] {aka AD-FSP, ATL-1, FSP1, HSN1D, SPG3, SPG3A}, Muc1 (mucin 1, transmembrane) [NCBI Gene 17829] {aka CD227, EMA, Muc-1}, Atf3 (activating transcription factor 3) [NCBI Gene 11910] {aka LRG-21}, Acsl4 (acyl-CoA synthetase long-chain family member 4) [NCBI Gene 50790] {aka 9430020A05Rik, ACS4, Facl4, Lacs4}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, PIN1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1) [NCBI Gene 5300] {aka DOD, UBL5}, BECN1 (beclin 1) [NCBI Gene 8678] {aka ATG6, VPS30, beclin1}, LPCAT3 (lysophosphatidylcholine acyltransferase 3) [NCBI Gene 10162] {aka C3F, LPCAT, LPLAT 5, LPLAT12, LPSAT, MBOAT5}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, AIFM2 (AIF family member 2, ferroptosis suppressor) [NCBI Gene 84883] {aka AMID, FSP1, PRG3}, Casp1 (caspase 1) [NCBI Gene 12362] {aka ICE, Il1bc}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], FKBP3 (FKBP prolyl isomerase 3) [NCBI Gene 2287] {aka FKBP-25, FKBP-3, FKBP25, PPIase}, TXNIP (thioredoxin interacting protein) [NCBI Gene 10628] {aka ARRDC6, EST01027, HHCPA78, THIF, VDUP1}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, DHODH (dihydroorotate dehydrogenase (quinone)) [NCBI Gene 1723] {aka DHOdehase, POADS, URA1}, ATF3 (activating transcription factor 3) [NCBI Gene 467], MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Aldh3a1 (aldehyde dehydrogenase family 3, subfamily A1) [NCBI Gene 11670] {aka Ahd-4, Ahd4, Aldh, Aldh3}, HDAC1 (histone deacetylase 1) [NCBI Gene 3065] {aka GON-10, HD1, KDAC1, RPD3, RPD3L1}, KRAS (KRAS proto-oncogene, GTPase) [NCBI Gene 3845] {aka 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, Rrm2 (ribonucleotide reductase M2) [NCBI Gene 20135] {aka R2}, Ascl1 (achaete-scute family bHLH transcription factor 1) [NCBI Gene 17172] {aka ASH1, Mash1, bHLHa46}, POU2F3 (POU class 2 homeobox 3) [NCBI Gene 25833] {aka Epoc-1, OCT-11, OCT11, OTF-11, PLA-1, PLA1}, NCAM1 (neural cell adhesion molecule 1) [NCBI Gene 4684] {aka CD56, MSK39, NCAM}, ATG3 (autophagy related 3) [NCBI Gene 64422] {aka APG3, APG3-LIKE, APG3L, PC3-96, hApg3}, SLC7A11 (solute carrier family 7 member 11) [NCBI Gene 23657] {aka CCBR1, xCT}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, PRDX5 (peroxiredoxin 5) [NCBI Gene 25824] {aka ACR1, AOEB166, B166, HEL-S-55, PLP, PMP20}, TFRC (transferrin receptor) [NCBI Gene 7037] {aka CD71, IMD46, T9, TFR, TFR1, TR}, Ptpmt1 (protein tyrosine phosphatase, mitochondrial 1) [NCBI Gene 66461] {aka 1110001D10Rik, 2810004N20Rik, PLIP}, ENO2 (enolase 2) [NCBI Gene 2026] {aka HEL-S-279, NSE}, Gpx4 (glutathione peroxidase 4) [NCBI Gene 625249] {aka GPx-4, GSHPx-4, PHGPx, mtPHGPx, snGPx}, CHCHD5 (coiled-coil-helix-coiled-coil-helix domain containing 5) [NCBI Gene 84269] {aka C2orf9, CHTM1, MIC14, MIX14}, ATR (ATR checkpoint kinase) [NCBI Gene 545] {aka FCTCS, FRP1, MEC1, SCKL, SCKL1} - **Diseases:** tumorigenesis (MESH:D063646), inflammatory tissue injury (MESH:D017695), GEMMs (MESH:D004482), deaths (MESH:D003643), lung cancer (MESH:D008175), Cancer (MESH:D009369), glioblastoma (MESH:D005909), porphyria (MESH:D011164), hepatorenal toxicity (MESH:D006530), TCPT (MESH:C536683), Hypoxia (MESH:D000860), LD (MESH:D052120), disease (MESH:D004194), bone metastasis (MESH:D009362), brain lesions (MESH:D001927), NE (MESH:D018358), ES-SCLC (MESH:D055752), Adenocarcinoma (MESH:D000230), LUAD (MESH:D000077192), inflammatory (MESH:D007249), oral cancer (MESH:D009062), mitochondrial dysfunction (MESH:D028361), ovarian cancer (MESH:D010051), Squamous cell carcinoma (MESH:D002294), neurotoxicity (MESH:D020258), WOS (MESH:C563636), Large-cell neuroendocrine carcinoma (MESH:D018287), necrosis (MESH:D009336), OS (MESH:C567932), tumorigenic (MESH:D002471), breast cancer (MESH:D001943), cytotoxicity (MESH:D064420), FRGs (MESH:C535507), NSCLC (MESH:D002289), stage (ES) (MESH:D062706) - **Chemicals:** peroxide (MESH:D010545), AF (MESH:D001310), ML210 (MESH:C000718731), SSZ (MESH:D012460), thiol (MESH:D013438), GSH (MESH:D005978), phospholipids (MESH:D010743), Mito-TEMPO (MESH:C555916), cysteine (MESH:D003545), PTX (MESH:D017239), sirolimus (MESH:D020123), sulforaphane (MESH:C016766), Erastin (MESH:C477224), bilirubin (MESH:D001663), withanolide (MESH:D054358), metalloporphyrin (MESH:D008665), MDA (MESH:D008315), FINO2 (-), Brusatol (MESH:C020237), aldehyde (MESH:D000447), cystine (MESH:D003553), ROS (MESH:D017382), NADH (MESH:D009243), altretamine (MESH:D006585), naphthoquinone (MESH:D009285), PUFA (MESH:D005231), isoprostanes (MESH:D028421), Hemin (MESH:D006427), pyrimidine (MESH:C030986), lipid hydroperoxides (MESH:D008054), SnPP (MESH:C032628), IKE (MESH:C000705694), 4-hydroxynonenal (MESH:C027576), selenocysteine (MESH:D017279), Withaferin A (MESH:C009684), lipid (MESH:D008055), heme (MESH:D006418), Sorafenib (MESH:D000077157), OXY (MESH:D010099), CO (MESH:D002248), ZnPP (MESH:C017803), CoQ10 (MESH:C024989), BSO (MESH:D019328), p-hydroxy cinnamaldehyde (MESH:C117045), IMP-1088 (MESH:C000723047), shikonin (MESH:C016101), Etoposide (MESH:D005047), biliverdin (MESH:D001664), Iron (MESH:D007501), isoorientin (MESH:C057912), ginkgetin (MESH:C077458), platinum (MESH:D010984), coumarins (MESH:D003374), iron oxide (MESH:C000499), ferrostatin-1 (MESH:C573944) - **Species:** Withania somnifera (ashwagandha, species) [taxon 126910], Mus musculus (house mouse, species) [taxon 10090], Lithospermum erythrorhizon (species) [taxon 34254], Homo sapiens (human, species) [taxon 9606] - **Mutations:** G12C, G12D - **Cell lines:** MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13040312/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13040312/full.md ## References 115 references — full list in the complete paper: https://tomesphere.com/paper/PMC13040312/full.md --- Source: https://tomesphere.com/paper/PMC13040312