{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:21:31Z","timestamp":1788787291922,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82574636;81902449"],"award-info":[{"award-number":["82574636;81902449"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hepatocellular carcinoma (HCC) remains challenging with limited immunotherapy response. Despite its clinical promise in advanced HCC, the mechanisms of icaritin, especially concerning ferroptosis induction and immune modulation, remain elusive. This study aims to determine if the antitumor effect of icaritin involves the induction of ferroptosis via NAD(P)H quinone oxidoreductase 1 (NQO1) and if it can augment the efficacy of programmed cell death 1 ligand 1 (PD\u2010L1) therapy by potentiating natural killer (NK) cell activity. Using human HCC cell lines (Huh7, Hep3B, PLC\/PRF\/5, SNU\u2010449, and MHCC97\u2010H) and two synergistic mouse models (Hepa1\u20106 and\n                    <jats:italic>SgPten\/c\u2010Met<\/jats:italic>\n                    ), we examined icaritin's inhibition of tumor growth and induction of ferroptosis via the NQO1 pathway, monitoring key markers (reactive oxygen species [ROS], glutathione peroxidase 4 [GPX4], ferritin heavy chain 1 [FTH1]). The NQO1 inhibitor dicoumarol was employed to validate the pathway. Tumor microenvironment (TME) remodeling was assessed through cancer\u2010associated fibroblasts (CAFs) markers and immune cell profiling, focusing on NK cell infiltration. Combination therapy with anti\u2010PD\u2010L1 was tested in\u00a0vivo. Icaritin significantly inhibited HCC growth in\u00a0vitro and in\u00a0vivo. Its antitumor effect was mediated by NQO1\u2010mediated ferroptosis, via elevated ROS, diminished mitochondrial membrane potential, and downregulated GPX4 and FTH1. Analysis of The Cancer Genome Atlas (TCGA) data revealed that NQO1 is overexpressed in human HCC tissues. Icaritin enhanced NK cell infiltration while reducing CAF abundance and suppressing recombinant focal adhesion kinase (FAK) and discoidin domain receptor 1 (DDR1) signaling. Notably, icaritin synergized with anti\u2010PD\u2010L1 therapy to enhance tumor suppression without increasing toxicity, correlating with potentiated NK cell immunity. Our findings demonstrate that icaritin triggered NQO1\u2010mediated ferroptosis and remodeled TME to enhance NK cell recruitment and PD\u2010L1 therapy efficacy. This provides rationale for evaluating icaritin\u2010based combination immunotherapy in HCC through dual action on ferroptosis and NK cell activation.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70230","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:30:57Z","timestamp":1773156657000},"page":"5339-5355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Icaritin Sensitizes Hepatocellular Carcinoma to\n                    <scp>PD<\/scp>\n                    \u2010\n                    <scp>L1<\/scp>\n                    Therapy by\n                    <scp>NQO1<\/scp>\n                    \u2010Dependent Ferroptosis Induction"],"prefix":"10.1002","volume":"40","author":[{"given":"Zhen","family":"Li","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine Capital Medical University  Beijing China"},{"name":"Center for Integrative Medicine, Beijing Ditan Hospital Capital Medical University  Beijing China"},{"name":"Cao Xian People's Hospital  Heze China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimeng","family":"Shang","sequence":"additional","affiliation":[{"name":"Center for Integrative Medicine, Beijing Ditan Hospital Capital Medical University  Beijing China"},{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Capital Medical University  Beijing China"},{"name":"Laboratory for Clinical Medicine Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghao","family":"Yin","sequence":"additional","affiliation":[{"name":"Beijing Youan Hospital Capital Medical University  Beijing 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