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The aim of the present study was to demonstrate that a mitochondria\u2010targeting and mtDNA G\u2010quadruplex\u2010binding ligand, BYB, induced mitochondrial calcium overload and ferroptosis in HeLa cells and showed potent <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> anticancer activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cellular functions and molecular mechanism were studied using cell viability assay, live\u2010cell imaging, western blotting, immunofluorescence, cell uptake, cell cycle arrest and apoptosis analysis, mitochondrial metabolism analysis, Comet assay, and wound\u2010healing analysis. Pharmacokinetic studies were conducted in rat. <jats:italic>In vivo<\/jats:italic> antitumor activity was studied in a cervical cancer HeLa cell xenograft mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Cellular results showed that BYB induced mitochondrial calcium overload, attributed to ligand\u2010induced mitochondrial dysfunction via the mechanism of inhibiting mitochondrial DNA replication and transcription. The expression of respiratory chain complexes was markedly downregulated in BYB\u2010treated HeLa cells. The respiratory chain function was also dysregulated. Mitophagy and mitochondrial calcium overload were induced in BYB\u2010treated HeLa cells. Mitochondrial calcium overload markedly induced mtROS production. The induced mtDNA stress activated cGAS\u2010STING pathway, leading to autophagy\u2010dependent ferroptosis. The antitumour efficacy of BYB, evaluated in a HeLa tumour xenograft mouse model, achieved over 60% tumour weight reduction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>BYB, via targeting mitochondria and mtDNA G\u2010quadruplexes, induced mitochondrial calcium overload and ferroptosis, exhibited high <jats:italic>in vivo<\/jats:italic> antitumour efficacy and low toxicity. It shows high potential to be a mitochondria\u2010targeting lead compound for chemical biology and drug discovery.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70061","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T08:39:45Z","timestamp":1746779985000},"page":"3923-3951","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A mitochondria\u2010targeting and G\u2010quadruplex structure\u2010binding ligand inducing calcium overload and ferroptosis in human cancer cells"],"prefix":"10.1111","volume":"182","author":[{"given":"Bo\u2010Xin","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Applied Biology and Chemical 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