{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:15:46Z","timestamp":1788419746746,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) has high malignancy, poor prognosis, and frequent chemo-resistance. Doxorubicin (DOX) has strong anti-tumor activity but severe systemic toxicity; baicalin (BAI) acts against HCC yet has poor solubility and low bioavailability. Marine sodium alginate (SA) is a biocompatible carrier for responsive nanomedicines. We fabricated pH\/GSH dual-responsive SA nanoparticles co-loaded with BAI and DOX (DOX\/BAI NPs), tested synergistic anti-HCC activity, and verified the correlation between the PI3K\/AKT\/FOXO3\u03b1 axis and DOX\/BAI NPs-induced ferroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Amphiphilic SA-SS-BAI was synthesized via cystamine disulfide bonds and self-assembled to encapsulate DOX. We characterized physicochemical traits, dual responsiveness, stability, and drug release. HepG2 cell uptake, endocytosis, and cytotoxicity were measured. Ferroptosis markers (ROS, Fe\n                      <jats:sup>2+<\/jats:sup>\n                      , GSH, MDA, SLC7A11, GPX4) were quantified. Western blot detected PI3K\/AKT\/FOXO3\u03b1 activity, with SC79 rescue for mechanistic validation. Pharmacokinetics, anti-tumor efficacy and biosafety were evaluated in H22 tumor-bearing mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SA-SS-BAI-4 formed uniform \u223c148\u00a0nm spherical DOX\/BAI NPs with good loading and encapsulation. NPs stayed stable physiologically and disassembled rapidly under low pH plus high GSH. Caveolae-dependent uptake was greatly boosted in HepG2 cells, yielding stronger growth inhibition than free drugs or physical mixtures. NPs triggered robust ferroptosis via ROS\/Fe\n                      <jats:sup>2+<\/jats:sup>\n                      buildup, elevated MDA level, GSH loss, and reduced SLC7A11\/GPX4. NPs treatment inhibited PI3K\/AKT\/FOXO3\u03b1 phosphorylation; SC79 reversed ferroptosis, confirming the correlative regulatory relationship of this pathway.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , NPs extended drug circulation, slowed H22 tumor growth, and markedly alleviated DOX-elicited hepatic and myocardial injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This dual pH\/GSH-responsive SA DOX\/BAI nanoplatform exerts synergistic anti-HCC effects by inducing ferroptosis, which is associated with PI3K\/AKT\/FOXO3\u03b1 axis suppression. The marine polysaccharide carrier overcomes BAI and DOX solubility\/toxicity defects, creates a practical HCC combinatorial nanotherapy, and defines a potential correlation between the PI3K\/AKT\/FOXO3\u03b1 regulatory axis and hepatic cancer ferroptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1905104","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:40:02Z","timestamp":1788417602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sodium alginate-based dual-responsive nanoparticles co-loaded with baicalin and doxorubicin induce ferroptosis in hepatocellular carcinoma associated with the PI3K\/AKT\/FoxO3\u03b1 axis regulation"],"prefix":"10.3389","volume":"14","author":[{"given":"Xining","family":"Li","sequence":"first","affiliation":[{"name":"School of Nursing and Medicine, Huzhou University","place":["Huzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Bian","sequence":"additional","affiliation":[{"name":"Neurobiology Laboratory, Wannan Medical College","place":["Wuhu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Neurobiology Laboratory, Wannan Medical College","place":["Wuhu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s41586-019-1703-9","article-title":"The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis","volume":"575","author":"Bersuker","year":"2019","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7775","DOI":"10.2147\/IJN.S460125","article-title":"Construction and evaluation of BAL-PTX co-loaded lipid nanosystem for promoting the anti-lung cancer efficacy of paclitaxel and reducing the toxicity of chemotherapeutic drugs","volume":"19","author":"Chen","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"11183","DOI":"10.2147\/OTT.S217624","article-title":"Baicalin inhibits cell viability, migration and invasion in breast cancer by regulating miR-338-3p and MORC4","volume":"12","author":"Duan","year":"2019","journal-title":"Oncotargets Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e14351","DOI":"10.15252\/emmm.202014351","article-title":"YAP\/TAZ and ATF4 drive resistance to sorafenib in hepatocellular carcinoma by preventing ferroptosis","volume":"13","author":"Gao","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.joim.2021.06.003","article-title":"The role of epithelial-mesenchymal transformation in hepatocellular carcinoma and the progress of TCM intervention therapy","volume":"19","author":"Li","year":"2021","journal-title":"J. Integr. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3831","DOI":"10.1021\/acs.molpharmaceut.2c00321","article-title":"Optimization and characterization of low-molecular-weight chitosan-coated baicalin mPEG-PLGA nanoparticles for the treatment of cataract","volume":"19","author":"Li","year":"2022","journal-title":"Mol. Pharm."},{"key":"B8","doi-asserted-by":"publisher","first-page":"119035","DOI":"10.1016\/j.jep.2024.119035","article-title":"Evaluation of efficacy, safety and underlying mechanism on traditional Chinese medicine as synergistic agents for cancer immunotherapy: a preclinical systematic review and meta-analysis","volume":"338","author":"Li","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B9","first-page":"4011","article-title":"LncRNA GAS6-AS2 facilitates tumor growth and metastasis of hepatocellular carcinoma by activating the PI3K\/AKT\/FoxO3a signaling pathway","volume":"12","author":"Liang","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2767","DOI":"10.21037\/tcr-24-1218","article-title":"SYT7 promotes breast cancer cells growth through the PI3K\/AKT pathway","volume":"13","author":"Luo","year":"2024","journal-title":"Transl. Cancer Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/s41598-023-51167-9","article-title":"Hesperetin promotes bladder cancer cells death via the PI3K\/AKT pathway by network pharmacology and molecular docking","volume":"14","author":"Lv","year":"2024","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.semcancer.2019.05.002","article-title":"Akt in cancer: mediator and more","volume":"59","author":"Revathidevi","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.3390\/molecules28041873","article-title":"Baicalin relieves LPS-induced lung inflammation via the NF-kB and MAPK pathways","volume":"28","author":"Shen","year":"2023","journal-title":"Molecules"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.1016\/j.cub.2018.06.010","article-title":"AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc-activity","volume":"28","author":"Song","year":"2018","journal-title":"Curr. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.1002\/ptr.7964","article-title":"Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling","volume":"37","author":"Sun","year":"2023","journal-title":"Phytother. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"135297","DOI":"10.1016\/j.ijbiomac.2024.135297","article-title":"Eco-friendly, pH-sensitive curcumin-loaded sodium alginate\/hydroxyapatite\/quaternary ammonium chitosan microspheres with enhanced antibacterial and antioxidant activities for fruit preservation","volume":"279","author":"Sun","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"732516","DOI":"10.1155\/2014\/732516","article-title":"Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells","volume":"2014","author":"Wang","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41419-021-02690-9","article-title":"GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2\/GPX4 axis","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.7150\/ijbs.81145","article-title":"AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis","volume":"19","author":"Wang","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1142\/S0192415X23510024","article-title":"Research progress of traditional Chinese medicine monomers in reversing multidrug resistance of breast cancer","volume":"51","author":"Wang","year":"2023","journal-title":"Am. J. Chin. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2284849","DOI":"10.1080\/15384047.2024.2284849","article-title":"Red ginseng polysaccharide promotes ferroptosis in gastric cancer cells by inhibiting PI3K\/Akt pathway through down-regulation of AQP3","volume":"25","author":"Wang","year":"2024","journal-title":"Cancer Biol. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"154881","DOI":"10.1016\/j.phytomed.2023.154881","article-title":"Baicalin induces ferroptosis in osteosarcomas through novel Nrf2\/xCT\/GPX4 regulatory axis","volume":"116","author":"Wen","year":"2023","journal-title":"Phytomedicine"},{"key":"B23","doi-asserted-by":"publisher","first-page":"108097","DOI":"10.1016\/j.intimp.2021.108097","article-title":"Baicalin protects against zearalenone-induced chicks liver and kidney injury by inhibiting expression of oxidative stress, inflammatory cytokines and caspase signaling pathway","volume":"100","author":"Xu","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4254\/wjh.v15.i2.129","article-title":"Current status and prospect of treatments for recurrent hepatocellular carcinoma","volume":"15","author":"Yang","year":"2023","journal-title":"World J. Hepatol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"13593","DOI":"10.2147\/IJN.S458761","article-title":"FA-PEG modified ZIF(Mn) nanoparticles loaded with baicalin for imaging-guided treatment of melanoma in mice","volume":"19","author":"Zhang","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1021\/acs.bioconjchem.4c00187","article-title":"Nanosized porphyrin-containing covalent organic polymer to enhance ferroptosis in photodynamic treatment of tumor cells via glutathione depletion","volume":"35","author":"Zhang","year":"2024","journal-title":"Bioconjug. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1016\/j.jcis.2024.121022","article-title":"Ultrasmall iridium-encapsulated porphyrin metal-organic frameworks for enhanced photodynamic\/catalytic therapy by producing reactive oxygen species storm","volume":"677","author":"Zhang","year":"2025","journal-title":"J. Colloid Interface Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.actbio.2025.01.024","article-title":"A self-assembling cytotoxic nanotherapeutic strategy for high drug loading and synergistic delivery of molecularly targeted therapies","volume":"191","author":"Zhang","year":"2025","journal-title":"Acta Biomater."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1905104\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:40:03Z","timestamp":1788417603000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1905104\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":28,"alternative-id":["10.3389\/fcell.2026.1905104"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1905104","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"1905104"}}