Inhibiting Wnt/β-catenin-mTOR Signaling Enhances Porphyrin Clearance in Murine Porphyrias with Hepatic Involvement

ABSTRACT: Background & Aims Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, oxidative stress, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation, protein aggregation, and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) signaling pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. Methods We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in mice fed DDC diet. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Results Wnt inhibition during DDC suppressed upregulation of porphyrin biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine, while also decreasing mTOR activity. Combined Wnt and GS deletion produced additive increases in autophagy and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Patient samples mirrored murine findings, with heme enzymes and β-catenin increased in porphyria cutanea tarda and autophagy inversely correlated with β-catenin expression. Conclusions Disrupting Wnt/GS signaling increases autophagy and reduces porphyrin formation, establishing a link between Wnt-driven metabolic signaling and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria."

ORGANISM(S): Mus musculus

PROVIDER: GSE325138 | GEO | 2026/09/11

REPOSITORIES: GEO