MASH-FLOW

Metabolic dysfunction-associated steatohepatitis (MASH) poses a significant challenge to global health due to its strong correlation with obesity, diabetes, and cardiovascular diseases. Current treatments, including lifestyle changes and therapies targeting inflammation and fibrosis, exhibit limited effectiveness. Based on the prominent roles of ferroptosis, lipotoxicity, and gut microbial dysbiosis in MASH, the MASH-FLOW project aims to propose an innovative therapeutic option by simultaneously targeting autophagy, metabolic imbalance, and cellular stress/senescence. The consortium believes that the triple therapy, which combines new antioxidant phytostilbenes derived from resveratrol (bio-produced by Team 4), with a caspase-2 inhibitor and an autophagy modulator developed by Teams 3 and 2 respectively, will have a synergistic effect to impede the progression of MASH. These compounds will undergo testing using innovative murine model that faithfully mimics the natural progression of MASH, as published by Team 1, with a perspective for clinical application. The project distinguishes itself with its innovative triple strategy, acting upstream of the pathological process to control extracellular matrix (ECM) remodeling. The methodology is detailed through five axes. With minimal identified risks and assured feasibility, the project aligns with the ANR "Biomedical Innovation" axis. The multidisciplinary consortium enjoys significant international renown due to its expertise in nutraceuticals, immunotherapy, and ECM research. It envisions MASH-FLOW making major advances in MASH pharmacology, paving the way for future clinical studies, and expects a high socio-economic impact. The project requests 985K€ for 48 months, reflecting the major contribution of permanent members from the four teams. MASH-FLOW represents a promising initiative with an innovative approach to addressing the complexities of MASH, offering potential breakthroughs in therapeutic interventions.