ABSTRACT: The liver, a pivotal organ in human metabolism, serves as a primary site for heme biosynthesis, critical for detoxification and drug metabolism. Maintaining precise control over heme production is paramount in healthy livers to meet high metabolic demands while averting potential toxicity from intermediate metabolites, notably protoporphyrin IX. Intriguingly, our recent research uncovers a disrupted heme biosynthesis process termed 'Porphyrin Overdrive' in cancers, fostering the accumulation of heme intermediates, potentially bolstering tumor survival. Here, we investigate heme and porphyrin metabolism in both healthy and oncogenic human livers, utilizing primary human liver transcriptomics and single-cell RNA sequencing (scRNAseq). Our investigations unveil robust gene expression patterns in heme biosynthesis in healthy livers, supporting electron transport chain (ETC) and cytochrome P450 function, devoid of intermediate accumulation. Conversely, liver cancers exhibit impaired heme biosynthesis and massive downregulation of cytochrome P450 expression. Notably, despite diminished drug metabolism, heme supply to the ETC remains largely unaltered or even elevated with cancer progression, suggesting a metabolic priority shift. Liver cancers selectively accumulate intermediates, absent in normal tissues, implicating their role in disease advancement as inferred by expression. Furthermore, our findings establish a link between diminished drug metabolism, augmented ETC function, porphyrin accumulation, and inferior overall survival in aggressive cancers, indicating potential targets for clinical therapy development.
