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Among the molecular mechanisms involved in CRC progression, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of pathways controlling tumor growth, invasion, therapeutic response, and cell survival. We previously demonstrated that miR-195-5p acts as a tumor suppressor in CRC by impairing proliferation, migration, invasion, and cell-cycle progression. However, its contribution to the regulation of apoptotic signaling remains incompletely understood. In this study, we aimed to investigate the role of miR-195-5p as a regulator of apoptotic signaling in CRC. Using membrane-based apoptosis arrays in CRC cell lines, we identified a miR-195-5p\u2013dependent modulation of multiple apoptotic mediators, with XIAP, BCL2, and BIRC5 (Survivin) emerging as common targets across independent prediction tools. Functional validation demonstrated that miR-195-5p overexpression significantly reduced the transcript and protein levels of these anti-apoptotic factors. This molecular modulation resulted in enhanced apoptotic activity, as evidenced by increased caspase-3\/7 activation, DNA fragmentation, and Annexin V-positive cell populations. Importantly, in vivo administration of miR-195-5p in an AOM\/DSS mouse model confirmed the downregulation of XIAP, BCL2, and BIRC5 (Survivin) in colonic tissues, supporting its translational relevance. Overall, our findings identified miR-195-5p as a key upstream regulator of apoptosis in CRC and highlighted its potential as a promising therapeutic strategy to overcome apoptosis resistance and improve treatment outcomes.<\/jats:p>","DOI":"10.1038\/s41420-026-03280-y","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T17:56:42Z","timestamp":1785261402000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-195-5p controls apoptotic cascade by regulating the XIAP\/BCL2\/Survivin network in colorectal cancer"],"prefix":"10.1038","volume":"12","author":[{"given":"Emanuele","family":"Piccinno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Scalavino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-0802","authenticated-orcid":false,"given":"Grazia","family":"Serino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"3280_CR1","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. 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