{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T06:54:07Z","timestamp":1779000847833,"version":"3.51.4"},"reference-count":98,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T00:00:00Z","timestamp":1768089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chemotherapy resistance in colorectal cancer (CRC) represents a critical clinical challenge leading to treatment failure and poor patient prognosis. Artemisinin is a natural product isolated from Artemisia annua, and its clinically relevant derivatives include dihydroartemisinin (DHA) and artesunate. Beyond their established antimalarial efficacy, both artemisinin and its derivatives\u2014collectively referred to as artemisinin-derived compounds (ADs)\u2014have been increasingly recognized for their unique potential to reverse multidrug resistance in cancer. Unlike previous reviews focusing on isolated mechanisms, this review systematically constructs a multidimensional, synergistic attack network centered on ADs to elucidate their integrated actions against chemotherapy-resistant CRC. Mechanistically, ADs suppress cancer stem cell (CSC)-associated resistance phenotypes while concurrently reshaping the tumor immune microenvironment, highlighting a functional coupling between stemness inhibition and immune remodeling. In parallel, this review presents apoptosis reactivation and ferroptosis induction as complementary, dual-track cell death strategies that collectively circumvent apoptosis resistance. Moreover, ADs exert \u201cone-strike\u2013multiple-effects\u201d through coordinated regulation of pro-survival signaling networks and immune-related pathways, including the induction of immunogenic cell death (ICD) and the modulation of immunosuppressive macrophage subsets. Beyond mechanistic insights, this review integrates emerging translational considerations, including clinical pharmacokinetics, safety and tolerability, formulation and delivery strategies, and rational combination therapy paradigms in CRC. Collectively, these findings position ADs as multi-dimensional modulators rather than a single-agent cytotoxic, providing a coherent mechanistic and translational rationale for their further development in chemotherapy-resistant CRC.<\/jats:p>","DOI":"10.3390\/molecules31020244","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T07:30:34Z","timestamp":1768203034000},"page":"244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multifaceted Attack Networks of Artemisinin in Reversing Chemoresistance in Colorectal Cancer"],"prefix":"10.3390","volume":"31","author":[{"given":"Mingfei","family":"Liu","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueling","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi 276005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, School of Medicine and Pharmacy, Ministry of Education, Ocean University of China, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kewu","family":"Zeng","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingchun","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi 276005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103191","DOI":"10.1016\/j.tice.2025.103191","article-title":"SUMO1 promotes malignancy and chemoresistance in colorectal cancer: Clinical and functional evidence","volume":"98","author":"Xu","year":"2025","journal-title":"Tissue Cell"},{"key":"ref_2","first-page":"142","article-title":"Epidemiology of colorectal cancer: A review with special emphasis on India","volume":"44","author":"Shivshankar","year":"2025","journal-title":"Indian J. 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