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Phenolic compounds are the most ubiquitously distributed pollutants, and are highly toxic to living organisms, however the detailed mechanism how phenols exert toxic effects remains elusive. Here, Escherichia coli and phloroglucinol are adapted as proxy to elucidate the molecular mechanism of phenols’ toxicity. We demonstrated that phloroglucinol complexed with iron and promoted the generation of hydroxyl radicals in Fenton reaction, leading to reducing power depletion and lipid peroxidation, and further leading to ferroptosis-like cell death of E. coli . This ferroptotic death can be triggered by various phenols in diverse organisms, from bacteria to mammalian cells. Furthermore, we demonstrated that phloroglucinol-induced ferroptosis suppressed tumor growth in mice effectively, indicating phloroglucinol as promising drug for therapy-resistant cancers. It’s also discovered that repression of this ferroptosis-like cell death benefited microbial degradation or production of desired phenolic compounds, showing great application potential in biotechnology field.