Molecular Anchors of Hepatic Detoxification State Fixation: Output-selective PXR-state disequilibrium within a disease-shaped ligand ecology

Detoxification state fixation (DSF) proposes that persistent hepatic de novo lipogenesis (DNL) in progressive metabolic liver disease reflects failed resolution of an originally adaptive detoxification-lipogenic state rather than simple continuation of nutrient- or insulin-driven pathway activation.

This work develops the molecular anchoring layer of the DSF framework. It proposes that progressive disease may involve a disease-shaped ligand ecology in which microbial amphiphiles, injury-associated retinoid flux, lipophilic stress mediators, and inflammatory tone reshape pregnane X receptor (PXR)-associated transcriptional output. Within this setting, output-selective PXR-state disequilibrium may allow impaired canonical detoxification capacity and persistent lipogenic signaling to coexist.

The model focuses on AKR1B10, SPTLC3, and SREBP1a as candidate molecular anchors of DSF. These nodes connect retinoid-carbonyl-DNL coupling, sphingolipid and membrane remodeling, human-relevant lipogenic transcription, lipid-droplet persistence, NADPH allocation, and glucose/G6P-associated metabolic routing within a self-maintaining hepatic state.

The central pathogenic transition is not activation of the adaptive program itself, but failed closure, impaired exit, and loss of reversibility. Protection becomes pathology only when hepatic rescue-and-repair mode loses reversibility.