Transcriptomic analysis reveals that resmetirom, a selective thyroid hormone receptor-beta agonist, simultaneously targets four critical disease mechanisms in metabolic dysfunction-associated steatohepatitis (MASH): dysregulated metabolism, chronic inflammation, progressive fibrosis, and hepatocyte death. The compound's multi-pathway intervention represents a significant advance beyond single-target MASH therapies that have largely failed in clinical development. This mechanistic insight helps explain resmetirom's clinical efficacy in Phase 3 trials, where it became the first FDA-approved treatment for MASH with moderate to advanced fibrosis. The transcriptomic data suggests the drug works through thyroid hormone signaling to restore hepatic metabolic homeostasis while simultaneously dampening inflammatory cascades and reducing collagen deposition. For the estimated 115 million adults worldwide with MASH, this represents a potential paradigm shift toward addressing the disease's underlying complexity rather than isolated symptoms. However, the liver-specific benefits must be weighed against potential systemic thyroid hormone effects, particularly in patients with existing thyroid conditions or cardiovascular risk factors.