Background: The epithelial‒mesenchymal transition (EMT) decisively contributes to human diseases such as organ fibrosis and tumors. However, the molecular mechanism triggering EMT remains unclear. Methods: We elucidated a novel self-amplifying feedback loop involving activating transcription factor 6 (ATF6) and Snail family transcriptional repressor 1 (SNAI1) and assessed its significant role in unfolded protein response (UPR)-dependent EMT. Multiple in vivo and in vitro models were applied, including mouse models of trauma and laser-induced lens injury and human lens epithelial explants from patients with senile cataracts. RNA sequencing was performed to comprehensively analyze the molecular mechanisms underlying UPR-dependent EMT, and heterozygous Atf6 knockout mice provided insights into the UPR-EMT crosstalk. The direct interaction between ATF6 and SNAI1 was verified via dual-luciferase assays. ATF6 expression was inhibited using AAV-shATF6 and melatonin (MLT) treatment in rodent models and cell cultures, respectively. Slit-lamp imaging, immunostaining, and western blotting were performed to assess EMT inhibition. Results: ATF6 expression was markedly upregulated in fibrotic cataracts, and ATF6 overexpression was sufficient to induce EMT-like changes both in vivo and in vitro. Similarly, compared with wild-type control mice, heterozygous Atf6 knockout mice presented ameliorated injury-induced EMT. Dual-luciferase assays combined with functional studies revealed a self-amplifying loop between ATF6 and SNAI1 that drives the uncontrollable progression of UPR-dependent EMT. Notably, MLT emerged as an effective inhibitor of UPR-dependent EMT and mitigated EMT-like alterations in parallel with Atf6 knockdown, suggesting that MLT could be leveraged to target the ATF6-SNAI1 self-amplifying loop and inhibit EMT in human diseases. Conclusions: Collectively, the results of this work demonstrate that the ATF6-SNAI1 self-amplifying loop acts as an important mediator of EMT and that MLT could be leveraged to target this loop and inhibit EMT in lens fibrosis.