MLKL (Mixed Lineage Kinase Domain Like Pseudokinase)

Altogether, our data suggest that MLKL in LPCs contributes to HCC initiation in the context of MASH, potentially involving its described non-canonical role within mitochondria, promoting oxidative stress, a cancer hallmark. This study provides new insights into evaluating the therapeutic potential of targeting MLKL, as its inhibition in LPCs may represent an effective strategy for treating MASH-related HCC.

VA may exert hepatoprotection by suppressing RIG-I, reducing TNF-α, and inhibiting RIPK1/RIPK3/MLKL-mediated necroptosis.

MLKL, associated with necroptosis, plays a crucial role in SCLC progression and may serve as a potential prognostic biomarker.

Particularly, we found overexpression of GLUT1, FLIP and downregulation of BAX, BAK, MLKL and CDX2 proteins in the cancer stem cell of early recurrence samples.We built a neural network based on the cancer stem cell protein signature (BAX, MLKL, FLIP, GLUT1 and CDX2 proteins) that delivers a high-performance prognostic classifier.How this study might affect research, practice or policy: Our results propose a clinically promising prognostic tool based on a five-protein stem cell signature that outperforms existing clinical and proposed transcriptomic based signatures for separation between risk groups.Moreover, our five-protein signature markers not only predict stem cell chemotherapy resistance and therefore tumour recurrence but also suggest potential therapeutic strategies. For instance, this approach could guide combinatorial treatments at high risk of chemoresistance, such as incorporating small molecule inhibitors targeting FLIP (currently in discovery phase) and GLUT1 (already under preclinical trial evaluation).

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic agents for various cancers, including cholangiocarcinoma (CCA) and colorectal cancer (CRC)...Notably, silencing of TNFR-I attenuated 5-FU-induced cell death in MLKL-knockdown cells. These findings provide novel insights into previously unrecognized roles of MLKL in modulating 5-FU responsiveness and highlight MLKL as a potential predictive and therapeutic target to improve 5-FU efficacy in precision cancer therapy.

This result preliminarily demonstrated that PD-L1 expression may be involved in antigen presentation in RAW264.7 cells with Kp infection. In conclusion, in Kp-infected RAW264.7 cells, PD-L1 mediates the increased apoptosis, necrosis, inflammatory responses, and CD4+ T cell activation, as well as inhibition of phagocytosis, and may be involved in antigen presentation, offering new therapeutic targets for Kp infection.

Gamma irradiation induces measurable physicochemical modifications in EA that underpin enhanced anticancer activity. These findings highlight IEA as a promising therapeutic candidate and illustrate the utility of irradiation for modulating polyphenolic compounds in cancer therapy.

Additionally, TSA enhanced T-cell-mediated anti-tumor immunity, as indicated by lower levels of CD8a+PD1+ and CD4+PD1+ regulatory T cells and higher levels of CD8a+Granzyme+, CD4+Granzyme+, CD8a+IFNγ+, and CD4+IFNγ+ cells in the spleen and tumor. In conclusion, TSA attenuates RIPK1/RIPK3/MLKL-signalling and reprograms the immunosuppressive TME, inhibiting OSCC progression and highlighting its potential as a therapeutic agent in clinical conditions.

This study establishes MLKL as a master regulator of anti-tumor immunity in OC, driving chemokine-mediated immune cell recruitment and TME reprogramming. The novel NecropImmScore is a multifaceted biomarker that effectively predicts prognosis, immunotherapy response, BRCA1 deficiency, and chemosensitivity, offering significant potential for guiding precision therapeutic strategies in OC.

Our results found that Hes could alleviate nephrotoxicity induced by nano-copper and inhibit PANoptosis in the kidney. The findings could contribute to a better understanding of nephrotoxicity induced by nano-copper and the underlying therapeutic action of hesperidin on nano-copper poisoning, which also established a foundation for further study of the toxic effects of nano-copper and the therapeutic effects of hesperidin.

Juglone inhibits the viability of KG-1a, MV-411, THP-1 and MOLM-13 cells, and induces apoptosis of MOLM-13 cells, the mechanism of which may be related to the inhibition of RIPK1/RIPK3/MLKL signaling pathway.

Exploiting these findings, we showed that a combination therapy activating RIPK3 with SMAC mimetics while suppressing caspase activity and providing type I IFN resulted in immune-mediated control of B cell tumors. Hence, reprogramming RIPK3 activity represents an attractive therapeutic opportunity to target B cell malignancies.