# Bisphenol F and Steatotic Liver Disease: Resolving the PXR Paradox Through Stress Pathway Mechanisms

## TL;DR

This paper explores how Bisphenol F causes liver disease through stress pathways, not just one receptor, and suggests new ways to assess and treat this condition.

## Contribution

The paper resolves the PXR paradox by identifying PXR-independent stress pathways as key drivers of BPF-induced steatotic liver disease.

## Key findings

- BPF-induced steatotic liver disease occurs mainly through oxidative stress and mitochondrial dysfunction.
- Therapeutic targets include Drp1, NLRP3/NF-κB, and AMPK-mTOR pathways for treating steatosis.
- Regulatory screening should include stress pathway biomarkers for better risk assessment of BPF.

## Abstract

Steatotic liver disease (SLD) represents a major global health burden, with environmental toxicants emerging as critical contributors alongside metabolic dysfunction. Bisphenol F (BPF), an increasingly prevalent replacement for bisphenol A, is widely detected in human biological samples and environment, yet its hepatotoxic mechanisms remain incompletely characterized. This review synthesizes current evidence on BPF-induced SLD, with a particular focus on resolving the “pregnane X receptor (PXR) paradox”, the mismatch between BPF’s weak direct activation of PXR and the PXR-like metabolic effects observed in vivo. Comprehensive analysis of mechanistic pathways reveals that BPF-induced SLD develops predominantly through PXR-independent mechanisms involving oxidative stress, endoplasmic reticulum dysfunction, Drp1-mediated mitochondrial fission, NLRP3/NF-κB-driven inflammation, dysregulated post-translational modifications, and epigenetic remodelling. These converging pathways collectively disrupt hepatic lipid metabolism, promote triglyceride accumulation, and establish a self-perpetuating cycle of metabolic dysfunction. Notably, weak indirect PXR modulation via oxidative stress represents a secondary, non-causal mechanism unsupported by functional validation. This framework distinguishes toxicant-induced steatosis from metabolic dysfunction-associated steatotic liver disease while highlighting critical evidence gaps—particularly the absence of causal PXR validation studies and human epidemiological data. Therapeutic opportunities exist at validated convergence points including mitochondrial dynamics (Drp1), inflammatory signalling (NLRP3/NF-κB), and energy metabolism (AMPK-mTOR), though combination strategies targeting multiple pathways will likely be required for durable disease reversal. These findings necessitate the expansion of regulatory screening paradigms to incorporate cellular stress pathway biomarkers alongside traditional nuclear receptor endpoints, ensuring comprehensive hepatotoxic risk assessment of emerging BPA substitutes.