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While HSC activation was a well-established driver of chronic liver fibrosis, its specific role and the triggers initiating it during the acute phase of malarial liver injury remain poorly defined. Notably, systemic copper accumulation occurred during\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      infection and can induce cuproptosis, a novel form of copper-dependent mitochondrial cell death. Given the liver\u2019s central role in copper metabolism and storage, coupled with the known sensitivity of HSC to copper perturbations, we hypothesized that malaria-induced hepatic copper overload may trigger cuproptosis, which subsequently acted as a key signal promoting HSC activation, thereby exacerbating acute liver injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using a\n                      <jats:italic>P.\u00a0berghei<\/jats:italic>\n                      ANKA (\n                      <jats:italic>Pb<\/jats:italic>\n                      )-infected C57BL\/6 mouse model, we modulated copper homeostasis in vivo with the copper ionophore disulfiram (DSF) and the copper chelator tetrathiomolybdate (TTM).\n                      <jats:italic>Parasitemia<\/jats:italic>\n                      and liver parasite burden were quantified to assess infection severity. Liver injury was systematically evaluated through histopathology, serum alanine transaminase\/aspartate aminotransferase (ALT\/AST) level, apoptosis detection (TUNEL), and fibrosis assessment (Sirius Red staining). Systemic inflammatory responses were assessed by measuring serum levels of tumor necrosis factor-alpha (TNF-\u03b1), interferon-gamma (IFN-\u03b3), and interleukin (IL)-10 using Enzyme-Linked ImmunoSorbent Assay (ELISA) kits. Hepatic copper levels were measured by rubeanic acid staining and inductively coupled plasma mass spectrometry (ICP-MS). To elucidate the underlying mechanisms, we analyzed the expression of key cuproptosis markers (FDX1, DLAT, and DLST) and hepatic stellate cell (HSC) activation markers (alpha smooth muscle actin (\u03b1-SMA) and Collagen I) using immunohistochemistry and immunofluorescence. Furthermore, the mRNA levels of profibrotic\/antifibrotic mediators in liver tissue were measured by quantitative polymerase chain reaction (qPCR) assay. Finally, to validate the mechanistic link between copper dysregulation and HSC activation, we conducted in vitro studies using\n                      <jats:italic>Pb<\/jats:italic>\n                      -infected red blood cells (iRBCs)-stimulated HSC cell line (HSCT6) treated with DSF-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      or TTM-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      complexes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Pb<\/jats:italic>\n                      infection triggered progressive hepatic copper accumulation and concomitant upregulation of key cuproptosis markers (FDX1, DLAT, and DLST), which paralleled worsening liver histopathology, enhanced HSC activation (\u03b1-SMA\/Collagen I\u2191), and increased collagen deposition (fibrosis). Critically, pharmacological elevation of copper levels using DSF exacerbated this pathological cascade: it amplified copper overload, further increased key cuproptosis marker expression (FDX1\/DLAT\/DLST\u2191), elevated parasitemia and liver parasite burden, and intensified HSC activation (\u03b1-SMA\/Collagen I\u2191), fibrosis, and liver pathology. Strikingly, DSF treatment significantly increased the proportion of activated (\u03b1-SMA\n                      <jats:sup>+<\/jats:sup>\n                      ) HSCs co-expressing FDX1, DLAT, or DLST, and shifted the cytokine balance toward profibrosis (TGF-\u03b2\/PDGF\u2191) while suppressing antifibrotic mediators (IFN-\u03b3\/HGF\u2193). In parallel, DSF treatment increased serum TNF-\u03b1 and IFN-\u03b3 levels while decreasing IL-10. Conversely, copper chelation with TTM effectively reversed these effects: it reduced hepatic copper, suppressed key cuproptosis marker expression and the prevalence of co-labeled HSC, alleviated HSC activation and fibrosis, and consequently improved liver function. This central mechanistic link between copper dysregulation and HSC activation was directly validated in vitro: in iRBC-stimulated HSCT6, DSF-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      complexes potentiated the upregulation of cuproptosis markers (FDX1, DLAT, and DLST), HSC activation markers (\u03b1-SMA and Collagen I), and profibrotic cytokines (TGF-\u03b2 and PDGF) while inhibiting antifibrotic cytokines (IFN-\u03b3 and HGF), whereas TTM-CuCl\n                      <jats:sub>2<\/jats:sub>\n                      treatment consistently attenuated these iRBC-induced changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate that malaria-induced hepatic copper overload triggers cuproptosis, which in turn directly activates HSC, thereby exacerbating acute liver injury. Pharmacological intervention with the copper chelator TTM effectively suppressed this pathogenic cascade and mitigated liver damage. Consequently, targeting copper-induced cuproptosis represents a novel therapeutic strategy for combating severe malaria-associated acute liver injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13071-026-07476-0","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T08:35:05Z","timestamp":1780907705000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Copper overload drives hepatic stellate cell activation via cuproptosis to exacerbate acute liver injury in murine malaria"],"prefix":"10.1186","volume":"19","author":[{"given":"Xiumei","family":"Mo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpeng","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haofeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajing","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minqiu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zujun","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"7476_CR1","volume-title":"World malaria report 2023","author":"WHO","year":"2024","unstructured":"WHO. 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