siRNA therapeutics for metabolic dysfunction-associated Steatohepatitis: Targets, delivery, clinical evidence, and translational challenges.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), is driven by interacting genetic, metabolic, inflammatory, and fibrogenic processes that complicate therapeutic development. Small interfering RNA (siRNA) is an emerging modality for sequence-specific suppression of genetically supported targets and intracellular proteins that are difficult to modulate with conventional drugs. Chemical modification and liver-directed delivery have improved siRNA stability and hepatic exposure. However, most MASH-directed programs remain preclinical or in early clinical development, and human data have not established consistent histological benefit. Major limitations include delivery to nonparenchymal cells, inefficient endosomal escape, off-target effects, immunogenicity, and uncertain long-term safety. This review critically evaluates target selection, delivery, clinical and preclinical evidence, unsuccessful programs, competing nucleic acid modalities, and combination strategies. The clinical role of siRNA in MASH remains to be established.