YTHDF2-mediated Distinct m6A Regulations Bifurcate Ferroptosis and Apoptosis in BHPF-induced Developmental Defects

Abstract N6-methyladenosine (m6A) is a critical regulator of RNA fate, but whether and how m6A executes its functions in different tissues remain largely obscure. Here we report YTHDF2 downregulation leading to various forms of tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, bisphenol A (BPA) substitutes have been widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant women participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular developmental defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. Both YTHDF2-mediated distinct m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs. Collectively, our findings demonstrate clear toxicity of BHPF during cardiovascular development via disrupting m6A/YTHDF2 regulatory axis and uncover a new layer of PCD regulation.