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Targeting the self-amplifying loop between ATF6 and SNAI1 to inhibit epithelial‒mesenchymal transition in fibrotic lesions

Published on Friday, 12 September 2025

Abstract

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.

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- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day and more orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);