Preclinical models demonstrated that TLR4 inhibition can attenuate NASH progression (less inflammation and fibrosis and even reduced HCC development). However, in clinical NASH, direct TLR4 blockade has not yet improved outcomes. No meaningful effect on glycemic control or liver histology was seen with JKB-121. Targeting LPS–TLR4 remains challenging, and combination strategies may be needed for T2D/NAFLD patients. Here, TLR4 is linked to metabolic dysfunction-associated steatohepatitis.