RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)

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

In conclusion, our findings indicate that CL-387785 induces necroptosis in tumor cells via the TRADD/RIPK1/NF-κB/CD80 signaling pathway, thereby sensitizing tumors to anti-PD-1 therapy. These results suggest that CL-387785 is a promising candidate for increasing tumor immunotherapy efficacy.

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

Ori as a natural small-molecule inhibitor of RIPK1, capable of concurrently mitigating neuroinflammation and necroptosis-two critical pathological processes underpinning AD. These findings strongly support Ori's potential as a disease-modifying therapeutic for AD.

Using D-galactose (D-gal)-treated NRK-52E cells and aged rats, we assessed rhein's effects with/without mTOR regulators (rapamycin/MHY1485) or etanercept (TNF-α inhibitor). In conclusion, rhein protected the kidneys by activating p-mTOR and downregulating TNF-α, necroptosis and autophagy. Rhein mitigates renal aging and fibrotic injury by targeting TNF-α-mediated autophagy-necroptosis crosstalk, positioning it as a novel multi-target therapeutic agent for age-related kidney injury.

Despite standard therapy with temozolomide (TMZ), prognosis remains poor, underscoring the need for novel therapeutic strategies...Furthermore, centratherin failed to sensitize GB cells to TMZ, suggesting distinct mechanisms of action, in spite of its remarked effect on inducing cell death in GB cancer stem-like cells. Overall, our findings highlight centratherin as a promising selective cytotoxic agent against GB, capable of inducing cell death and disrupting key malignant phenotypes, which may be advantageous for GB treatment.

We delineated the PANoptosis landscape in ccRCC and developed a robust PRG score with strong prognostic and immunological relevance. RBCK1 functions as a key oncogenic regulator and potential therapeutic target. These findings offer a valuable framework for precision risk assessment and treatment optimization in ccRCC.

Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.

These findings suggest that DNMT1/3B-skewed methylation at the SOX9/DEFA5 promoters may be counteracted by ten-eleven translocation-mediated counter-demethylation. Collectively, our data indicate that afatinib modulates Paneth-like differentiation markers via DNA methylation-dependent repression of SOX9/DEFA5 and DNA methylation-independent induction of OSR1/RIP140 in Caco-2 cells, which may be relevant to crypt-associated epithelial function and gastrointestinal safety.

However, the additional involvement of RIPK1 and induction of RIPK3 clustering in select cell lines suggest that multiple pathways may be triggered upon OpA treatment. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment.

This suppression of necroptosis was associated with reduced microgliosis, neuroinflammation and enhanced neuronal survival within the striatum. These findings highlight the potential of Pazo as a neuroprotective agent against HD by leveraging its antioxidant, anti-inflammatory, immune-modulating, and anti-necroptotic properties.

See also the graphical abstract(Fig. 1).