The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis

Villano, Gianmarco; Novo, Erica; Turato, Cristian; Quarta, Santina; Ruvoletto, Mariagrazia; Biasiolo, Alessandra; Protopapa, Francesca; Chinellato, Monica; Martini, Andrea; Trevellin, Elisabetta; Granzotto, Marnie; Cannito, Stefania; Cendron, Laura; De Siervi, Silvia; Guido, Maria; Parola, Maurizio; Vettor, Roberto; Pontisso, Patrizia

doi:10.1016/j.molmet.2024.101889

Cited by 6 publications

(1 citation statement)

References 57 publications

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“…In Par2KO mice, the HBVX response was dramatically alleviated [ 75 ]. In a diet-induced non-alcoholic steatohepatitis (NASH) model, treatment with 1-PPA, a recently identified Par2 inhibitor, effectively suppressed the PAR2—C/EBP-β—SerpinB3 axis, resulting in protection against NASH development and progression [ 76 ].…”

Section: Introductionmentioning

confidence: 99%

Par2-mediated responses in inflammation and regeneration: choosing between repair and damage

Reches,

Piran

2024

Inflamm Regener

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The protease activated receptor 2 (Par2) plays a pivotal role in various damage models, influencing injury, proliferation, inflammation, and regeneration. Despite extensive studies, its binary roles— EITHER aggravating injury or promoting recovery—make a conclusive translational decision on its modulation strategy elusive. Analyzing two liver regeneration models, autoimmune hepatitis and direct hepatic damage, we discovered Par2’s outcome depends on the injury’s nature. In immune-mediated injury, Par2 exacerbates damage, while in direct tissue injury, it promotes regeneration. Subsequently, we evaluated the clinical significance of this finding by investigating Par2’s expression in the context of autoimmune diabetes. We found that the absence of Par2 in all lymphocytes provided full protection against the autoimmune destruction of insulin-producing β-cells in mice, whereas the introduction of a β-cell-specific Par2 null mutation accelerated the onset of autoimmune diabetes. This pattern led us to hypothesize whether these observations are universal. A comprehensive review of recent Par2 publications across tissues and systems confirms the claim drafted above: Par2’s initial activation in the immune system aggravates inflammation, hindering recovery, whereas its primary activation in the damaged tissue fosters regeneration. As a membrane-anchored receptor, Par2 emerges as an attractive drug target. Our findings highlight a crucial translational modulation strategy in regenerative medicine based on injury type.

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Section: Introductionmentioning

confidence: 99%

Par2-mediated responses in inflammation and regeneration: choosing between repair and damage

Reches,

Piran

2024

Inflamm Regener

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Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis

Guan,

Zou,

Yang

et al. 2024

Molecular Metabolism

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Protease activated receptor 2 as a novel druggable target for the treatment of metabolic dysfunction-associated fatty liver disease and cancer

Villano,

Pontisso

2024

Front. Immunol.

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Metabolic dysfunction-associated fatty liver disease (MAFLD) is spreading worldwide, largely due to unhealthy lifestyles that contribute to the rise in diabetes, metabolic syndrome, and obesity. In this situation, the progression of injury to metabolic steatohepatitis can evolve to cirrhosis and, eventually, to hepatocellular carcinoma (HCC). It is well known that serine protease enzymes with different functions in cellular homeostasis act as signaling molecules that regulate liver inflammation by activating the protease-activated receptors (PARs) family members, expressed on the cellular plasma membrane. Among them, PAR2 plays a central role in the activation of signaling pathways in response to changes in the extracellular microenvironment. Experimental data have provided evidence that PAR2 is involved not only in inflammatory response but also in insulin resistance, lipid metabolism, and cancer. The major aims of this narrative review are addressed to assess PAR2 involvement in inflammation, metabolism, and liver disease progression and to explore possible therapeutic strategies, based on PAR2 inhibition, in order to prevent its biological effects in the context of MAFLD and cancer.

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The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis

Cited by 6 publications

References 57 publications

Par2-mediated responses in inflammation and regeneration: choosing between repair and damage

Par2-mediated responses in inflammation and regeneration: choosing between repair and damage

Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis

Protease activated receptor 2 as a novel druggable target for the treatment of metabolic dysfunction-associated fatty liver disease and cancer

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