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Hypoxia and pyroptosis are closely linked to malignant progression and may shape tumour biology and the immune microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Pyroptosis- and hypoxia-related genes were obtained from GeneCards and MSigDB, and PHRGs were defined as the intersection of pyroptosis- and hypoxia-associated gene sets for subsequent consensus clustering. Transcriptomic profiles and survival information for CRC were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Pyroptosis- and hypoxia-related molecular subtypes were identified using consensus clustering. Least absolute shrinkage and selection operator and Cox regression analyses were applied to construct a prognostic signature. Key signature genes were preliminarily assessed at the expression level in paired CRC and adjacent normal tissues using qRT-PCR (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 pairs) and western blotting (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096 pairs). Given the limited sample size and lack of stage- or subtype-stratified validation, these experiments provide preliminary expression-level support rather than functional confirmation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients were classified into four PHRG-related molecular subtypes with distinct prognoses and biological characteristics, with PHRGcluster C2 showing the worst outcome. A total of 1578 pyroptosis- and hypoxia-related differentially expressed genes (PHRDEGs) were identified across the four PHRGclusters. A six-gene prognostic signature (PHRDEGscore) was then established in the TCGA cohort. Patients with a high PHRDEGscore had shorter survival, which was validated in external cohorts (GSE39582 and GSE17536). The low-PHRDEGscore group exhibited higher immune infiltration (e.g., activated CD8+\u2009and CD4+\u2009T cells), and an exploratory association with immunotherapy response was observed in a non-CRC immunotherapy-treated cohort (IMvigor210). Experimental analyses indicated higher mRNA levels of HES4, SHROOM2, and OXCT1 in CRC tissues than in adjacent normal tissues (qRT-PCR,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 pairs), and increased protein expression of HES4 and SHROOM2 (western blotting,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096 pairs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identified hypoxia- and pyroptosis-related molecular patterns and a six-gene prognostic signature in CRC. The observed associations are correlative and hypothesis-generating. Prospective validation in independent, well-annotated clinical cohorts is needed before any clinical application can be considered.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12672-026-04970-w","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T13:47:04Z","timestamp":1776865624000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of pyroptosis and hypoxia related molecular subtypes and a prognostic signature in colorectal cancer"],"prefix":"10.1007","volume":"17","author":[{"given":"Hui","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YuanWang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"issue":"3","key":"4970_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. 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