Inhibition of vascular smooth muscle cells (VSMCs) proliferation without dysregulating endothelial cells (ECs) may provide an ideal therapy for in-stent restenosis. Due to its anti-proliferation effect on VSMCs and pro-endothelium effect, arsenic trioxide (ATO) has been used in a drug-eluting stent in a recent clinical trial. However, the underlying mechanism by which ATO achieves this effect has not been determined. In the present work, we showed that ATO induced apoptosis in VSMCs but not in ECs. Mechanistically, ATO achieved this through modulation of cellular metabolism to increase lysophosphatidic acid (LPA) in VSMCs, while LPA concentration was stable in ECs. The elevated LPA facilitated the nuclear accumulation and initiated the transcriptional function of Yes-associated protein (YAP) in VSMCs. YAP regulated the transcription of N6-Methyladenosine (m6A) modulators (Mettl14 and Wtap) to increase the m6A methylation levels of apoptosis-related genes to induce their high expression and exacerbate VSMCs apoptosis. On the other hand, YAP nuclear accumulation in ECs was not observed. Collectively, our data exhibited the molecular process involved in selective apoptosis of VSMCs induced by ATO. Schematic diagram of ATO selectively induced apoptosis between VSMCs and ECs. [Display omitted] • Arsenic trioxide (ATO) has the selective inhibiting role for VSMCs over ECs. • Apoptosis is the leading death manner induced by ATO in VSMCs. • ATO directly binds to PLA 2 G 6 and autotaxin to increase the LPAin VSMCs to initiate the transcriptional function of YAP. • The activated YAP induced a higher m6A methylation level of apoptosis-related genes to exacerbate apoptosis of VSMCs. [ABSTRACT FROM AUTHOR]