ABSTRACT 1‐Naphthol (1‐NAP) is a pervasive environmental pollutant and metabolite of polycyclic aromatic hydrocarbons, and the insecticide carbaryl, posing significant human health risks. Despite its recognized toxicity, the direct contribution of 1‐NAP to metabolic liver disease pathogenesis remains unclear‐a critical gap given the rising global incidence of metabolic dysfunction‐associated steatotic liver disease (MASLD) in non‐obese individuals (“lean MASLD”). Here, through integrated cross‐species models (zebrafish, mice, human hepatocytes), transcriptomics, and functional analyses, we demonstrate that 1‐NAP directly targets hepatic carbonic anhydrase 3 (CA3). Drug affinity responsive target stability assays confirm direct 1‐NAP‐CA3 binding, leading to CA3 stabilization. This interaction drives transcriptional upregulation of CD36 via a CA3‐dependent mechanism. Functional studies reveal that 1‐NAP not only upregulates CD36 expression but also promotes its CA3‐dependent translocation to the plasma membrane, resulting in enhanced CD36‐mediated fatty acid uptake. This leads to hepatic steatosis and, following chronic exposure, progressive fibrosis characterized by α‐SMA and Col1a1 upregulation and collagen deposition. Pharmacological inhibition of CA3 with acetazolamide reverses steatosis and injury, while dietary curcumin acting in a CD36‐dependent manner ameliorates both lipid accumulation and fibrogenesis. These findings establish proof‐of‐concept that the CD36 node is druggable. Our work identifies the evolutionarily conserved CA3‐CD36 axis as a central, targetable pathway through which an environmental pollutant drives obesity‐independent MASLD, providing a mechanistic foundation for lean MASLD and advocating for the development of specific CD36 inhibitors as a therapeutic strategy.
Chen et al. (Wed,) studied this question.