Journal article
Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement
Autophagy
08/19/2026
DOI: 10.1080/15548627.2026.2716960
PMID: 42618898
Abstract
Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, 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 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) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. 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. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.
ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).
Details
- Title: Subtitle
- Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement
- Creators
- Oluwashanu Balogun - Children's Hospital of PittsburghPamela Cornuet - University of PittsburghElizabeth Lee - University of PittsburghGarima Patel - University of PittsburghAbdul-Shahid Raheem - University of PittsburghJunjie Zhu - University of PittsburghAmber Marie Vandevender - University of PittsburghAnila P Ashokan - Rutgers, The State University of New JerseyRaheleh Nasrollahi - Rutgers, The State University of New JerseyRaymond E West III - University of PittsburghOctavia Peck Palmer - University of Pittsburgh School of MedicineJia-Jun Liu - University of Pittsburgh School of MedicineThomas D Nolin - University of PittsburghClaudette St Croix - University of Pittsburgh School of MedicineXiaochao Ma - University of PittsburghGrant Bullock - University of IowaSilvia Liu - University of PittsburghSatdarshan P Monga - University of PittsburghDonna Beer Stolz - University of PittsburghMichael Jurczak - University of PittsburghM Bishr Omary - Rutgers, The State University of New JerseyKari Nejak-Bowen - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Autophagy
- DOI
- 10.1080/15548627.2026.2716960
- PMID
- 42618898
- NLM abbreviation
- Autophagy
- ISSN
- 1554-8635
- eISSN
- 1554-8635
- Publisher
- Taylor & Francis
- Grant note
- University of Pittsburgh Office of the Senior Vice Chancellor, Health Sciences NIH Office of the Director: S10OD028540 University of Pittsburgh Center for Research Computing and Data: S10OD028483 NIDDK: R01 DK124412, P30 DK120531, R01 DK116548, R01 DK126875 University of Pittsburgh Small Molecule Biomarker Core facility: RRID:SCR_025218 NIGMS: R35 GM159862
This work was funded by NIDDK [R01 DK124412] to Kari Nejak-Bowen, NIDDK [P30 DK120531] to Satdarshan P Monga, NIDDK [R01 DK116548] to M Bishr Omary, NIGMS [R35 GM159862] to Silvia Liu, and in part by NIDDK [R01 DK126875] to Xiaochao Ma. This research was also supported in part by University of Pittsburgh Center for Research Computing and Data, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH[S10OD028483]. This project used the service of the University of Pittsburgh Small Molecule Biomarker Core facility [RRID:SCR_025218], which was supported, in part, by University of Pittsburgh Office of the Senior Vice Chancellor, Health Sciences, and the NIH Office of the Director [S10OD028540].
- Language
- English
- Electronic publication date
- 08/19/2026
- Academic Unit
- Pathology
- Record Identifier
- 9985219867702771
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