{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:27:18Z","timestamp":1791329238285,"version":"4.3.1"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Aging is the primary risk factor for prostate cancer (PCa), characterized biologically by a systemic collapse of proteostasis networks. Paradoxically, rather than succumbing to this decline, PCa cells exploit it, developing a \u201cproteostasis addiction\u201d to cope with persistent intrinsic stress. This review elucidates this paradox through three conceptual frameworks: the dynamic transition from age-related functional decay to tumorigenic hijacking; the specificity of oncogenic protein regulation; and the functional dichotomy (or \u201cdouble-edged sword\u201d) of proteostatic components in tumor suppression\n                    <jats:italic>versus<\/jats:italic>\n                    promotion. We examine how declining molecular chaperone networks are co-opted to selectively stabilize the androgen receptor (AR) and its variants. Furthermore, we explore how the ubiquitin\u2013proteasome system (UPS) is re-engineered\n                    <jats:italic>via<\/jats:italic>\n                    E3 ligases and deubiquitinases (DUBs) to orchestrate the precise turnover of tumor suppressors and oncoproteins. Special attention is given to chaperone-mediated autophagy (CMA), which undergoes a reversal from age-associated suppression to hyperactivation in advanced PCa, thereby fueling metabolic adaptation and therapy resistance. Beyond the intracellular context, we discuss how proteostatic imbalances drive the senescence-associated secretory phenotype (SASP) to remodel the tumor microenvironment. Finally, we assess emerging therapeutic strategies, arguing that precision modulation of specific proteostasis nodes\u2014such as distinct E3\/DUBs or CMA pathways\u2014represents a promising frontier to overcome castration-resistant prostate cancer (CRPC).\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1755668","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:13:56Z","timestamp":1768454036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["The proteostasis paradox: from systemic collapse in aging to pathway-specific addiction in prostate cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Danhong","family":"Guo","sequence":"first","affiliation":[{"name":"Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyao","family":"Peng","sequence":"additional","affiliation":[{"name":"Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlan","family":"Yu","sequence":"additional","affiliation":[{"name":"Urology Department, Sir Run Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/j.cell.2008.03.038","article-title":"Chemokine signaling via the CXCR2 receptor reinforces senescence","volume":"133","author":"Acosta","year":"2008","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.ccr.2010.04.027","article-title":"Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor","volume":"17","author":"Andersen","year":"2010","journal-title":"Cancer Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"802","DOI":"10.18632\/aging.100613","article-title":"Enhancing protein disaggregation restores proteasome activity in aged cells","volume":"5","author":"Andersson","year":"2013","journal-title":"Aging"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1056\/NEJMoa1315815","article-title":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","volume":"371","author":"Antonarakis","year":"2014","journal-title":"N. 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