Bisphenol F induces intestinal epithelial injury through hsa_circ_0003655-mediated dual-axis disruption of cytoplasmic and organellar calcium homeostasis.

As a primary substitute for bisphenol A (BPA), the potential threats of environmental exposure to bisphenol F (BPF) on intestinal health have raised significant concerns. However, the underlying regulatory mechanisms involving circular RNA (circRNA) remain unclear. Utilizing whole-transcriptome sequencing, this study discovered that hsa_circ_0003655 was significantly upregulated in response to BPF toxicity in both human colonic epithelial cells (NCM460) and mouse models, exhibiting high cross-species conservation. Mechanistically, BPF disrupted cellular calcium homeostasis through a hsa_circ_0003655-mediated "dual-axis" pathway. This dual-axis comprises a CACNA1H-driven extracellular calcium influx and a SND1-driven intracellular calcium redistribution. Specifically, BPF not only promoted extracellular calcium influx by increasing the methylation level of CACNA1H via hsa_circ_0003655, but also, with hsa_circ_0003655 acting as a competing endogenous RNA (ceRNA), facilitated the transfer of cytosolic calcium into mitochondria and the endoplasmic reticulum through the hsa-miR-212-5p/SND1 axis. Furthermore, we revealed that this SND1-mediated process drives organelle calcium overload by specifically upregulating SERCA3 and MICU1. This dual-axis disruption ultimately led to organelle calcium overload and subsequent cellular injury. In summary, this study elucidates the critical role of hsa_circ_0003655 in mediating BPF-induced intestinal toxicity, providing novel biomarkers for the risk assessment of environmental pollutants and offering potential strategies for targeted interventions against intestinal damage.