{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T20:57:14Z","timestamp":1788209834052,"version":"build-2803163510"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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. Pharmacol."],"abstract":"<jats:p>Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative modality within the targeted protein degradation (TPD) landscape, inducing spatial proximity between E3 ubiquitin ligases and proteins of interest (POIs) to hijack the ubiquitin-proteasome system (UPS). Unlike traditional occupancy-driven inhibitors, this catalytic, event-driven mechanism enables the targeting of historically \u201cundruggable\u201d proteomes and circumvents acquired resistance. However, the field faces formidable challenges, including suboptimal pharmacokinetic profiles, the stoichiometric \u201chook effect,\u201d and a disproportionate reliance on a limited pool of E3 ligases (notably cereblon (CRBN) and von Hippel-Lindau (VHL)). This review critically examines PROTAC core principles and provides a nuanced functional categorization across oncology, immune modulation, neurodegenerative diseases, and basic research. We further evaluate three pivotal technical strategies\u2014degrader architecture innovations, conditional activation modalities, and advanced delivery platforms\u2014while systematically appraising current clinical progress. Finally, we discuss key limitations and future translational directions, aiming to provide a realistic roadmap for the next-generation of TPD therapeutics.<\/jats:p>","DOI":"10.3389\/fphar.2026.1815569","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:48:07Z","timestamp":1779256087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Research progress and future perspectives in proteolysis-targeting chimeras"],"prefix":"10.3389","volume":"17","author":[{"given":"Nuofan","family":"Wu","sequence":"first","affiliation":[{"name":"School of Food and Drug, Shenzhen Polytechnic University","place":["Shenzhen, China"]},{"name":"School of Biological Science and Engineering, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihui","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Food and Drug, Shenzhen Polytechnic University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhong","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Food and Drug, Shenzhen Polytechnic University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Food and Drug, Shenzhen Polytechnic University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders: the past is prologue","volume":"21","author":"B\u00e9k\u00e9s","year":"2022","journal-title":"Nat. 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