International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 33-41 http://medscipublisher.com/index.php/ijmms 36 4.2 Role of the endoplasmic reticulum and mTOR pathway The Endoplasmic Reticulum (ER) is crucial for protein folding and trafficking, and its dysfunction is a key contributor to hepatic cystogenesis. Mutations in genes such as PRKCSH and SEC63, which encode ER-associated proteins, result in defective protein folding and glycosylation, particularly of polycystin-1. This disruption leads to ER stress, which promotes cyst formation through cellular apoptosis and dysregulated proliferation (Besse et al., 2017). The mammalian target of rapamycin (mTOR) pathway is another critical player. mTOR signaling regulates cell growth, proliferation, and autophagy. Dysregulation of mTOR has been observed in cystic cholangiocytes, with increased mTOR activity contributing to cyst growth. Preclinical studies have demonstrated that mTOR inhibitors, such as rapamycin, can reduce cyst proliferation and size in experimental models. This pathway provides a promising therapeutic target for managing PLD and related conditions. This study investigates the role of dysregulated pathways, including mTOR signaling, in liver cyst development, providing a foundation for therapeutic targeting (Ellis et al., 2022). 4.3 Genetic and epigenetic interactions The genetic landscape of liver cysts includes mutations in PKD1, PKD2, PRKCSH, SEC63, and other genes associated with polycystic liver and kidney diseases. Recent studies highlight the role of "second-hit" somatic mutations in the pathogenesis of cysts, where loss of heterozygosity in cyst-lining cells triggers uncontrolled proliferation (Wills et al., 2016). Epigenetic modifications, such as DNA methylation and histone acetylation, are emerging as important factors in cystogenesis. Aberrant methylation patterns have been observed in cystic epithelium, potentially silencing tumor suppressor genes and promoting cyst growth. Additionally, microRNAs (miRNAs) are gaining attention for their role in regulating gene expression in cystic liver diseases. For instance, dysregulated miRNA expression can modulate pathways involved in cholangiocyte proliferation and apoptosis, offering potential biomarkers and therapeutic targets (Figure 1) (Masyuk et al., 2021). Figure 1 Hepatic cystogenesis (Adoptrd from Masyuk et al., 2021) Image caption: (a) patients and (b–d) animal models with different forms of PLD (Adoptrd from Masyuk et al., 2021)
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