{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:07:48Z","timestamp":1791346068230,"version":"4.3.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>As the economy grows, there is a growing emphasis on food safety. While the health benefits of chlorogenic acid (CGA) are recognized, safe dosages and potential liver cell damage from excessive CGA consumption are not well studied. This study aims to determine the safe and effective dose range of CGA and understand how it causes toxicity in hepatocyte at half-maximal inhibitory concentration (IC50).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study assessed the impact of various CGA concentrations on liver cells, examining growth, viability, toxicity, energy metabolism, and colony formation using Real-Time Cell Analysis (RTCA), CCK-8, lactate dehydrogenase (LDH) assays, and Seahorse XF96. It established CGA\u2019s IC50 for cell viability and identified differentially expressed proteins via proteomics. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the signaling pathways associated with the differentially expressed proteins. Further validation of the molecular mechanisms was performed using flow cytometry, Western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Finally, CGA was injected into Kunming (KM) mice via the tail vein for acute toxicity testing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this study, 200\u00a0\u00b5M of CGA significantly reduced LDH release and increased the mitochondrial oxygen consumption rate (OCR) in hepatocytes, but it did not affect the extracellular acidification rate (ECAR). Additionally, 200\u00a0\u00b5M of CGA slightly promoted hepatocyte growth; however, at 300\u00a0\u03bcM, CGA nearly completely inhibited the clonogenic capacity of hepatocytes, and at 600\u00a0\u03bcM, it significantly impeded hepatocyte growth. The IC50 of CGA for hepatocyte activity was determined to be 613.1\u00a0\u00b5M.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments indicated that incubation with CGA at its IC50 concentration for 96\u00a0h resulted in the arrest of L-02 cells in the S phase of the cell cycle and induced apoptosis. Further investigation revealed that the IC50 concentration of CGA, through the depletion of free iron within hepatocytes, significantly reduced the expression of iron-sulfur cluster subunits in mitochondrial complexes I-III and disrupted the oxidative-reductive homeostasis of hepatocytes, ultimately leading to hepatotoxicity. Interestingly, N-Acetyl-L-cysteine (NAC) or ferric citrate reduced hepatocyte toxicity from excessive CGA. All mice survived after receiving CGA injections at doses up to 125\u00a0mg\/kg. The semi-lethal concentration (LD\n                      <jats:sub>50<\/jats:sub>\n                      ) for Kunming mice was 382.28\u00a0mg\/kg.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that the antioxidant and iron-chelating properties of CGA determine its role in either liver protection or toxicity at varying concentrations, providing valuable insight for its rational dietary and clinical use.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1740609","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:50:46Z","timestamp":1771926646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Safe dosage and potential risks of chlorogenic acid: insights from in vitro and in vivo 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