Blocking Wnt pathway may offer new treatment route for liver porphyrias

A cell signaling pathway called Wnt-beta-catenin may serve as a potential therapeutic target in porphyrias that affect the liver, a new study suggests.

Blocking this pathway attenuated heme production and activated the body’s natural cellular cleanup process, reducing the toxic buildup of porphyrins in a mouse model of porphyria. In a separate genetic mouse model, Wnt inhibition also reduced liver scarring in females.

The study, “Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement,” was published in Autophagy.

Recommended Reading

July 8, 2026 News by Margarida Maia, PhD

New oral drug shows big promise in small trial as a porphyria treatment

Porphyrias disrupt heme production and damage the liver

Porphyrias are a group of rare metabolic disorders caused by defects in one of the eight enzymes involved in the production of heme, the molecule in red blood cells that helps carry oxygen. These defects cause porphyrins and other heme precursors to accumulate in cells to toxic levels, primarily in the liver and bone marrow.

Chronic exposure to these porphyrins can lead to liver injury, inflammation, scarring (cirrhosis), and potentially liver cancer. Current treatments can reduce acute symptomatic attacks but are limited by cost and safety concerns.

“Given these limitations, emerging therapies targeting cellular processes that are directly or indirectly dysregulated in porphyria are urgently needed,” the researchers wrote.

Prior studies have shown that a liver-specific deletion of the beta-catenin protein, a messenger in the Wnt signaling pathway, can reduce porphyrin precursor buildup and liver injury in an induced model of porphyria.

A key target in Wnt-beta-catenin signaling is the enzyme glutamine synthetase. Mouse models harboring beta-catenin mutations developed liver cancer alongside strong glutamine synthetase production. At the same time, reducing beta-catenin in these models reversed tumor development and decreased mTOR activation, establishing a link between beta-catenin and mTOR activity. mTOR acts as a cellular sensor that promotes cell growth and blocks autophagy.

Separately, beta-catenin-deficient livers were shown to have increased autophagy, the cell’s internal recycling system that clears out unwanted molecules, and prior research showed that Wnt signaling can suppress proteins involved in autophagy. However, whether increased autophagy actually cleared porphyrins remained unknown.

Researchers test Wnt inhibition in mouse models

Based on these findings, the researchers hypothesized that blocking Wnt-beta-catenin signaling and glutamine synthetase might reduce heme production and promote porphyrin clearance from cells via autophagy.

To test this, the team combined Wnt inhibition with the drug Wnt-C59 and/or genetic deletion of glutamine synthetase specifically in liver cells in male mice. The animals were fed a diet containing DDC, a compound that induces porphyria-like liver injury.

In the DDC-fed mice, blocking Wnt signaling suppressed the increased activity of heme-production genes, reduced the buildup of porphyrin intermediates, and boosted autophagy. Deleting glutamine synthetase attenuated porphyrin production. Combining the two approaches further boosted autophagy and reduced porphyrin buildup.

Suppressing Wnt, glutamine synthetase, or both also reduced levels of porphobilinogen, a porphyrin precursor and marker for diagnosing porphyria, to levels comparable to those in mice fed a normal diet.

To test whether inhibiting mTOR would have a similar protective effect, mice were treated with rapamycin, a molecule that inhibits mTOR. However, porphyrin accumulation in the liver worsened in DDC-fed mice, unlike the effects seen with Wnt or glutamine synthetase inhibition.

To evaluate the benefit of inhibiting Wnt signaling in a clinically relevant model of porphyria, the researchers used Fech mice, a model of erythropoietic protoporphyria, a rare porphyria subtype. After two weeks of treatment with the Wnt inhibitor, female Fech mice, but not male mice, showed a 9% decrease in liver-to-body weight ratio, along with reduced liver scarring.

Consistent with the DDC model, Wnt inhibition reduced mTOR activation in female mice, thereby further increasing autophagy and mitigating liver injury in female Fech mice. The team noted that female Fech mice had lower pre-treatment porphyrin levels and liver injury than males, which may have made them more responsive to treatment.

Wnt inhibition partially restores mitochondrial cleanup

Researchers also examined mitophagy, a type of autophagy that clears damaged mitochondria, the cell’s energy producers. While DDC treatment reduced mitophagy, consistent with liver injury, it was partially restored by Wnt inhibition. Deleting glutamine synthetase also partially improved mitochondrial efficiency in DDC-treated mice.

Finally, to assess the clinical relevance of these findings, the team examined liver samples from healthy individuals and patients with porphyria, including porphyria cutanea tarda (PCT). In PCT samples, the heme-producing enzymes ALAS1 and ALAD were elevated compared to healthy controls. Higher ALAS1 correlated with diffuse, cytoplasmic beta-catenin, and an autophagy marker was elevated in samples with faint or diffuse beta-catenin staining. The researchers cautioned that the small number of human samples limits how broadly these findings can be applied.

“These results suggest that PCT patients may benefit from [beta]-catenin inhibition to suppress heme biosynthesis enzymes and activate autophagy,” the team noted.

“By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver,” they concluded. “Targeting the Wnt-[beta]-catenin-[glutamine synthetase] axis offers a rational, novel, mechanism-based strategy for mitigating [liver] injury in porphyrias with [liver] manifestations.”