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Ferroptosis is characterised by iron\u2010dependent lipid peroxidation, while pyroptosis is an inflammatory cell death mediated by gasdermin proteins. Recent studies reveal extensive crosstalk between these pathways. This review establishes the first hierarchical framework coupling the autophagy bridge function (ferritinophagy\u2010mitophagy\u2010cyclic GMP\u2010AMP synthase (cGAS)\u2010stimulator of interferon genes (STING) axis) with the p53\/signal transducer and activator of transcription 3 (STAT3)\/Nuclear factor erythroid 2\u2013related factor 2 (NRF2) transcriptional hub, creating a unified decision\u2010making network absent in prior reviews. Crosstalk mechanisms include the reactive oxygen species (ROS)\u2010NOD\u2010like receptor protein 3 (NLRP3) positive feedback loop, caspase cross\u2010activation, and iron metabolism\u2010inflammasome integration. Preclinically, the transferrin\u2010targeted nanosystem Tf\u2010LipoMof@PL increased intratumoral iron\/ROS 3\u20135\u2010fold, inducing robust antitumour immunity, while Ginsenoside Rh3 suppressed colorectal cancer growth in\u00a0vivo via STAT3\/p53\/NRF2\u2010mediated dual death induction. We critically address STAT3's paradoxical roles\u2014promoting Gasdermin E (GSDME)\u2010mediated pyroptosis in oesophageal cancer while suppressing NLRP3 via suppressor of cytokine signalling 3 (SOCS3) feedback in acute respiratory distress syndrome (ARDS)\u2014highlighting cell type\u2010specific feedback architectures that dictate phenotypic outcomes. For therapeutic translation, we propose a Translational Priority Matrix ranking nanodelivery systems (Tf\u2010LipoMof@PL) and dual\u2010function small molecules (N6F11) as the highest priority for intrahepatic cholangiocarcinoma (iCCA)\/triple\u2010negative breast cancer (TNBC), while deprioritising metal photosensitizers pending resolution of cardiac retention toxicity (0.8\u2009\u03bcg\/g myocardium in Good Laboratory Practice (GLP) studies). The \u201cregistration gap\u201d stems from iron burst\u2010release (&gt;\u200980% within 30\u2009min) and species\u2010specific biomarker failures. We advocate replacing murine malondialdehyde (MDA)\/glutathione (GSH) ratios with human\u2010anchored metrics (ferritin heavy chain 1 (FTH1)\/solute carrier family 40 member 1 (SLC40A1) expression, serum ferritin) and propose a \u201cCross\u2010Death AI Platform\u201d integrating network pharmacology (OmniPath\/STRING), GraphSAGE deep learning (AlphaFold2 structures), and organoid validation to stratify patients and predict optimal drug combinations. By resolving spatiotemporal heterogeneity and implementing AI\u2010guided precision medicine, we can transform multi\u2010target interventions from empirical strategies into rational, patient\u2010specific regimens, bridging the gap between preclinical promise and clinical success in cancers and neurodegenerative diseases.<\/jats:p>","DOI":"10.1111\/jcmm.71138","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T03:50:16Z","timestamp":1776829816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Crosstalk Mechanisms Between Ferroptosis and Pyroptosis and Their Applications in Diseases: From Molecular Networks to Clinical Strategies"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9429-1657","authenticated-orcid":false,"given":"Wei\u2010Yi","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Clinical Pathalogy of Yanbian Hospital of Yanbian University Yanbian University  Yanbian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u2010yao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery of Second Hospital of Jilin University Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang\u2010wang","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery of Second Hospital of Jilin University Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery of Second Hospital of Jilin University Jilin University  Changchun 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