{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:33:43Z","timestamp":1790354023578,"version":"4.1.0"},"reference-count":150,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation Project of Xinjiang Uygur Autonomous Region","award":["2024D01C266"],"award-info":[{"award-number":["2024D01C266"]}]},{"name":"Xinjiang Uygur Autonomous Region Tianchi Talent Introduction Program-Young Doctor","award":["5105250184p"],"award-info":[{"award-number":["5105250184p"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471260"],"award-info":[{"award-number":["32471260"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Multidrug resistance (MDR) is a central cause of chemotherapy failure and tumor recurrence and metastasis, and its mechanism involves enhanced drug efflux, target mutation, upregulation of DNA repair and remodeling of the tumor microenvironment. ABC transporter protein (P-gp, MRP, and BCRP)-mediated efflux of drugs is the most intensively researched aspect of the study, but the first three generations of small-molecule reversal agents were stopped in the clinic because of toxicity or pharmacokinetic defects. Natural products are considered as the fourth generation of MDR reversal agents due to their structural diversity, multi-targeting and low toxicity. In this paper, we systematically summarize the inhibitory activities of monoterpenes, sesquiterpenes, diterpenes and triterpenes against ABC transporter proteins in in vitro and in vivo models and focus on the new mechanism of reversing drug resistance by blocking efflux pumps, modulating signaling pathways such as PI3K-AKT, Nrf2, NF-\u03baB and remodeling the tumor microenvironment. For example, Terpenoids possess irreplaceable core advantages over traditional multidrug resistance (MDR) reversers: Compared with the first three generations of synthetic reversers, natural\/semisynthetic terpenoids integrate low toxicity (mostly derived from edible medicinal plants, half-maximal inhibitory concentration IC50 &gt; 50 \u03bcM), high target specificity (e.g., oleanolic acid specifically inhibits the ATP-binding cassette (ABC) transporter subtype ABCC1 without cross-reactivity with ABCB1), and multi-mechanistic synergistic effects (e.g., \u03b2-caryophyllene simultaneously mediates the dual effects of \u201cABCB1 efflux inhibition + apoptotic pathway activation\u201d). These unique characteristics enable terpenoids to effectively circumvent key limitations of traditional synthetic reversers, such as high toxicity and severe drug\u2013drug interactions. Among them, lupane-type derivative BBA and euphane-type sooneuphanone D (triterpenoids), as well as dihydro-\u03b2-agarofuran-type compounds and sesquiterpene lactone Conferone (sesquiterpenoids), have emerged as the core lead compounds with the greatest translational potential in current MDR reverser research, attributed to their potent in vitro and in vivo MDR reversal activity, low toxicity, and excellent druggable modifiability. At the same time, we point out bottlenecks, such as low bioavailability, insufficient in vivo evidence, and unclear structure\u2013activity relationship and put forward a proposal to address these bottlenecks. At the same time, the bottlenecks of low bioavailability, insufficient vivo evidence and unclear structure\u2013activity relationship have been pointed out, and future research directions such as nano-delivery, structural optimization and combination strategies have been proposed to provide theoretical foundations and potential practical pathways for the clinical translation research of terpenoid compounds, whose clinical application still requires further in vivo validation and translational research support.<\/jats:p>","DOI":"10.3390\/ph19010146","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:12:04Z","timestamp":1768403524000},"page":"146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Terpenoids: Emerging Natural Modulators for Reversing ABC Transporter-Mediated Multidrug Resistance in Cancer Chemotherapy"],"prefix":"10.3390","volume":"19","author":[{"given":"Lanfei","family":"Ma","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Mahemuti","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanhong","family":"Lan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7572-2991","authenticated-orcid":false,"given":"Jianxiong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0436-4277","authenticated-orcid":false,"given":"Wenfang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-001X","authenticated-orcid":false,"given":"Zhengding","family":"Su","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-6096","authenticated-orcid":false,"given":"Jinyao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5626-2216","authenticated-orcid":false,"given":"Aytursun","family":"Abuduwaili","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Xinjiang Agricultural University, Urumqi 830052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4363-7642","authenticated-orcid":false,"given":"Ayitila","family":"Maimaitijiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Institute of Materia Medica, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"ref_1","first-page":"115","article-title":"Cancer statistics in China, 2015","volume":"66","author":"Chen","year":"2016","journal-title":"CA Cancer J. 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