1-Naphthol Drives Liver Steatosis and Fibrosis via the CA3-CD36 Axis Independent of Obesity

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.