MAP2K3 (Mitogen-Activated Protein Kinase Kinase 3)

MKK6 directly phosphorylated BCL2L13 at serine 426, enhancing the interaction between BCL2L13 and LC3B, which, in turn, promoted mitophagy, inhibited oxidative phosphorylation (OXPHOS), and prevented tumor growth. Our studies not only revealed that MKK6-BCL2L13 phosphorylation at the interorganellar site can affect mitochondrial quality in tumorigenicity but also might provide a potential therapeutic strategy for LUAD treatment.

In vivo, endothelial GPRC5B deficiency significantly accelerated tumor growth and neovascularization, phenotypes that were effectively reversed by the p38 inhibitor SB202190. Clinical specimens corroborated reduced GPRC5B expression and increased microvessel density in MetS-associated PCa. Collectively, our findings establish endothelial GPRC5B downregulation as a key molecular driver promoting pathological angiogenesis via the MKK3/6-DUSP1-p38 axis, suggesting that targeting this signaling cascade offers a promising therapeutic strategy for managing MetS-associated PCa aggression.

Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

Using high-throughput screening, we established that combining p38 inhibitors with the BRAF inhibitor dabrafenib showed strong synergy in vitro, including in cells resistant to dabrafenib and trametinib that had acquired a secondary TP53 mutation. Overall, our findings suggest an oncogenic link between the MAPK and p38/MAPK14 pathways and that combining p38 pathway inhibitors with dabrafenib-targeted therapy could improve treatment outcomes for aggressive thyroid cancers. However, more specific and effective p38 inhibitors are required to fully harness this potential.

This process can be reversed by the p38 inhibitor Adezmapimod, further confirming that its apoptosis-inducing effect is dependent on the p38 MAPK pathway. This study not only validates the reliability of patient-derived organoids in personalized drug screening but also uncovers the potential therapeutic value of Toyocamycin for TNBC, providing a novel model and theoretical foundation for the precision treatment of TNBC.

Clinical correlation analysis of CRC patient specimens revealed a strong positive correlation between USP13 and MKK3 expression levels, with elevated USP13 expression associated with advanced disease stage. Our findings not only establish the USP13-MKK3-p38 axis as a crucial molecular pathway in CRC progression but also identify USP13 as a promising therapeutic target.

Oral administration of Lactobacillus for six months reduced OS marker levels and inhibited NRF2/KEAP1, p38 MAPK, and JNK signalling pathways in CRC patients after surgery. These findings suggest that Lactobacillus may contribute to CRC management by modulating oxidative stress.

In addition, the results of biochemical indexes further verified that the overall changes in plasma ALT, AST, TBIL, DBIL, TRIG, ALP, LDH, GGT, CREA, UA, UREA, CK, HBD, and CHOL were significantly smaller in the TMF-treated groups than in the DDP-treated groups. These findings collectively position TMF as a promising therapeutic candidate combining robust antitumor efficacy with favorable safety characteristics for the treatment of cervical cancer.

Our predictors, together with the rapid experimental validations, demonstrates a feasible strategy for identifying activating variants in kinases in a time frame that would enable clinical decisions.

CK2α is significantly overexpressed in the tumor tissue of female CRC patients and shows a strong age-related correlation. These findings suggest a sex- and age-specific regulatory mechanism potentially influenced by estrogen signaling or menopause. Such dimorphisms underscore the need for sex-specific strategies in CRC biomarker development and therapy.

TNF signaling was identified through network pharmacology analysis as the anti-inflammatory mechanism of MFZD, and validated by WB results showing that MFCS treatment reduced TNF-α-induced protein expression of p-MKK3/MKK6, p-p38, TRAF2, p-p65, and VCAM1. This study demonstrated that MFZD exerts anti-degenerative and anti-inflammatory potency against OA and revealed the TNF-α/TRAF2/NF-κB signaling related anti-inflammatory mechanism of MFZD for the first time, offering mechanistic insights into its potential in OA therapy.

RACK1 serves as a gatekeeper restraining inflammation-driven ADM transformation, with its downregulation constituting an early molecular event in PDA pathogenesis. The RACK1-MAP2K3 axis orchestrates malignant transition through simultaneous NF-κB activation (inflammatory priming) and MAPK hyperactivation (proliferative drive). Our findings nominate RACK1 as both a stratification biomarker for high-risk pancreatic lesions and a druggable node for intercepting preneoplastic progression.