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In the present study, we further elaborated on the mechanism by comparing differences in antimalarial activity and resistance-associated molecular expression profiles between ART alone and combination therapy in blood and tissues of <jats:italic>Mdr1a<\/jats:italic> wild-type (WT) and knockout (KO) mice infected with either sensitive or resistant malarial parasites.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We evaluated the effects of monotherapy and combination therapy in WT and KO mice infected with sensitive and resistant <jats:italic>P.\u00a0berghei<\/jats:italic> K173 strains. The mRNA expressions of multi-resistance proteins (Mrp1, 2, 4, 5) and breast cancer resistance proteins (Bcrp) were detected. Hemoglobin levels, mRNA expressions of cytokines including tumor necrosis factor-\u03b1 (IFN-\u03b1), interferon-\u03b1 (IFN-\u03b1), and interleukin (IL-1\u03b2) in blood and tissues, and redox balance (ROS\/GSH levels), as well as gene or protein expression of signaling pathway (PI3K\/AKT-mTOR and MAPK) were investigated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In drug-resistant mice, combination therapy maintained the highest survival (100%) and inhibition (30%) rates and the lowest parasitaemia percentage (approximately 20.0%), irrespective of <jats:italic>Mdr1a<\/jats:italic> gene status. Furthermore, combination reshaped the spatial and ART resistance-phenotypic disparities in Mrps and Bcrp mRNA expressions (with a fold change ranging from 1.35 to 38.03), ROS\/GSH balance (ranging from 1.02-fold to 10.18-fold), hemoglobin levels (ranging from 1.04-fold to 1.20-fold), and cytokine profiles (ranging from 1.14-fold to 37.79-fold) induced by ART alone, which were partially dysregulated by <jats:italic>Mdr1a<\/jats:italic> deficiency. Monotherapy and combination exert oppositely regulatory effects on the PI3K\/AKT-mTOR pathway in a tissue-, <jats:italic>Mdr1a<\/jats:italic> genotype-, and parasite sensitivity\/resistance-dependent manner (ranging from 1.52-fold to 84.00-fold). Specifically, CHR reversed ART-induced changes via PI3K\/AKT protein inhibition (ranging from 1.20-fold to 63.00-fold), which was contingent on P-gp functionality. Finally, mitogen-activated protein kinase (MAPK) pathway was involved in the antagonistic regulation between ART alone and combination therapy in a P-gp-independent manner (ranging from 1.39-fold to 16.69-fold).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The efflux pump function of P-gp is probably not a critical factor in the mechanism by which CHR reverses ART resistance. Instead, CHR acts as a homeostasis stabilizer with dual functions: it disrupts <jats:italic>Plasmodium berghei<\/jats:italic> K173 resistance to ART driven by both ABC transporters and the heme-ROS\/GSH axis, in which the non-transport function of P-gp on ART is involved.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1186\/s13071-025-07018-0","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:01:55Z","timestamp":1760014915000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chrysosplenetin acts as a homeostasis stabilizer with dual-function in shattering Plasmodium berghei K173 resistance to artemisinin driven by both ABC transporters and heme-ROS\/GSH axis"],"prefix":"10.1186","volume":"18","author":[{"given":"Hongyan","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Bo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Heng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"7018_CR1","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1016\/S0140-6736(18)30324-6","volume":"391","author":"EA Ashley","year":"2018","unstructured":"Ashley EA, Pyae Phyo A, Woodrow CJ. 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