ZFP90 Serves as a Transcriptional Brake on NF-κB Signaling to Attenuate Diet-Induced MASLD Progression

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become increasingly common, a trend driven by obesity, excess nutritional intake, and dysfunctional adipose tissue. While continuous dietary stress triggers adipose-tissue-derived lipotoxicity and disrupts hepatic metabolic homeostasis and provokes inflammation, the transcriptional scaffolds that mitigate this lipotoxicity remain incompletely understood. We investigated the role of zinc finger protein 90 (ZFP90) in defending against diet-induced metabolic stress and MASLD pathogenesis. Methods: Wild-type and ZFP90-knockout mice were subjected to a high-fat diet (HFD) to model nutrient-overload-induced MASLD. Hepatic phenotypes were characterized using metabolic profiling and RNA sequencing. Mechanistic dynamics were evaluated through protein interaction assays, and clinical relevance was validated using human MASLD liver biopsies. Results: ZFP90 deficiency significantly accelerated HFD-induced steatosis, systemic insulin resistance, and inflammatory infiltration. Crucially, ZFP90 depletion drove severe white adipose tissue (WAT) dysfunction, characterized by impaired lipogenic capacity, exacerbated lipolysis, and diminished local insulin signaling. This was accompanied by a pro-inflammatory secretory shift in WAT, evident from decreased Adipoq and increased Cd68/Ccl3 expression. In the liver, transcriptomic analysis revealed a profound induction of pathways related to fatty acid uptake and cytokine signaling. Mechanistically, ZFP90 forms a repressive complex with TRIM28, acting as a crucial molecular brake on NF-kB signaling. Loss of ZFP90 unleashes p65-mediated hyper-inflammation. Clinically, hepatic ZFP90 expression is significantly upregulated in patients with MASLD. Conclusions: ZFP90 is a novel regulator of immunometabolic homeostasis under dietary stress. By forming of complex with Trim28 to inhibit the nuclear translocation of NF-κB, ZFP90 suppresses pro-inflammatory responses and protects the liver from obesity-associated systemic lipotoxicity. These findings provide critical insights into the adipo-hepatic axis and highlight ZFP90 as a promising therapeutic target to mitigate the progression to metabolic dysfunction-associated steatohepatitis (MASH).