MAP3K5 and Insulin resistance: This insufficiency is exacerbated in heterogeneous patient populations where the contribution of ASK1-mediated stress may vary, and where other pro-fibrotic pathways, driven by metabolic comorbidities like severe insulin resistance, become dominant and are not adequately addressed by ASK1 inhibition alone (Powell et al., 2021; Peng et al., 2024; Zhu and Cai, 2025).