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Unc-51-like kinase 1 (ULK1), a central regulator of autophagy, has emerged as a potential therapeutic node in cancer but remains poorly understood in TNBC. Here, we investigated the proteomic consequences of pharmacological ULK1 modulation in MDA-MB-231 TNBC cells. Cells were treated with the ULK1 activator LYN-1604 or inhibitor MRT68921 at EC\u2085\u2080 concentrations. Autophagic activity, validated through LC3B immunoblotting and fluorescence microscopy, increased under both treatments. Quantitative label-free LC-MS\/MS proteomics prioritized 182 and 196 candidate differentially abundant proteins in response to LYN-1604 and MRT68921, respectively. ULK1 activation primarily altered transcriptional regulation and suppressed translation, whereas inhibition was associated with enrichment of immune-related pathway and vesicle-mediated transport. Five proteins consistently downregulated across both treatments (PSIP1, AGO2, MORF4L1, HNRNPC, and SETD2) were prioritized as candidate hubs based on shared regulation across perturbations and network ranking using CytoHubba\/MCC. These candidates mapped to autophagy-associated pathway modules\/terms related to MET\u2013FAK signaling, extracellular matrix\u2013related processes, and mitochondrial Ca\u00b2\u207a handling\/transport. These findings suggest that ULK1 modulation, regardless of direction, associated with proteomic changes in pathways linked to tumor-promoting networks. Our study provides a comprehensive proteomic framework linking ULK1 perturbation to transcriptional, immune, and epigenetic regulation, and highlights downstream effectors as candidate targets for future functional and translational validation in TNBC.<\/jats:p>","DOI":"10.1007\/s12032-026-03274-x","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T11:45:49Z","timestamp":1772538349000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["ULK1-driven autophagy modulation alters tumor-promoting pathways in triple-negative breast cancer"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2444-4258","authenticated-orcid":false,"given":"Merve Gulsen","family":"Bal Albayrak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6438-7385","authenticated-orcid":false,"given":"Sevinc","family":"Yanar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-4022","authenticated-orcid":false,"given":"Tu\u011fcan","family":"Korak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9675-3714","authenticated-orcid":false,"given":"Gurler","family":"Akpinar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8527-2096","authenticated-orcid":false,"given":"Murat","family":"Kasap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"3274_CR1","first-page":"7","volume":"68","author":"RL Siegel","year":"2018","unstructured":"Siegel RL, Miller KD, Jemal A. 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