PPM1A (Protein Phosphatase Mg2+/Mn2+ Dependent 1A)

Cystin-1 intracellular trafficking and function are regulated by a myristoyl-electrostatic switch mechanism. Cystic kidneys in three individuals with homozygous CYS1 pathogenic variants provide further support that cystin-1 deficiency causes polycystic kidney disease that phenocopies ARPKD.

Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.

Exploiting this 'death switch' offers a novel therapeutic framework through three principal strategies: (1) inducing pyroptosis to eliminate apoptosis-resistant cells, (2) utilizing pyroptosis-induced inflammation to enhance immune checkpoint inhibitor efficacy, and (3) developing targeted therapeutics that directly modulate these switch molecules. Although controlling pyroptosis-associated inflammation remains challenging, understanding and manipulating the apoptosis-to-pyroptosis transition provides an innovative approach to overcome drug resistance and develop more effective cancer treatments.

Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.

Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin.​ Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.

Consequently, MKRN2-mediated PPP2CA repression increased β-catenin phosphorylation and decreased its protein levels, causing the inactivation of Wnt signaling pathway and amplification of apoptosis in ccRCC cells. This study demonstrated that the E3 ligase activity of MKRN2 had a pivotal role in regulating the PPP2CA-β-catenin-Wnt pathway and granted MKRN2 as a candidate tumor suppressor in ccRCC.

SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation. Targeting both SLC7A11-AS1 and activin A may offer a potential therapeutic strategy for overcoming gemcitabine resistance in PDAC.

In conclusion, our findings highlight a novel mechanism of action for forskolin and support a potential role of this natural compound in combination with current conventional agent daunorubicin in the treatment of KMT2A-r AML.

Our study reveals that Triptolide effectively inhibits OC progression by targeting the PPP2CA-ITGA5 axis, mitigating lactate-driven metabolic reprogramming.

The main aim is to explain why and how the different Houge-Janssens syndrome subtypes biochemically and clinically overlap, providing a framework for understanding new variants and new subtypes that will be found in the future. Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found.

TRIM47 promoted paclitaxel resistance in ovarian cancer by inducing PPM1A degradation and activating the TGF-β pathway.

IGFG can achieve simultaneous intervention of HE by inhibit inflammatory reaction, regulate immunity, promote hepatocyte regeneration, reduce hepatocyte apoptosis, maintain liver function homeostasis and antiviral function. It presents the network regulation mechanism of mutual influence and complex correlation. This study provides a scientific basis for IGFG in the treatment of patients with HE.