SRPK1 (SRSF Protein Kinase 1)

This study underscores the pivotal contribution of RNA splicing in BCa metastasis, with SNW1 serving as a key mediator. The identification of key regulatory molecules provides valuable insights into potential therapeutic targets for clinical intervention in metastatic BCa.

Additionally, in silico screening reveals that 4'-O-Methylochnaflavone interacts with SRPK1, which effectively stabilizes SRPK1 and alleviates PA-induced ferroptosis. Collectively, these findings underscore the critical role of PA in regulating endothelial cell ferroptosis via SRPK1 S-palmitoylation and p53 activation, providing potential therapeutic strategies for dyslipidemia-related erectile dysfunction.

Enhanced sampling method─"random accelerated molecular dynamics (RAMD)", including PMF evaluation and path analysis─was employed to explore the egression route and investigate the exit dynamics of small molecules from the binding pocket. This study lays the groundwork for novel therapeutic design methodologies while improving our molecular-level understanding of protein-protein-small-molecule interactions linked to carcinogenesis.

These findings highlight tetrandrine's dual profile: a promising natural antiangiogenic agent with demonstrable efficacy, yet with significant cardiotoxic and developmental liabilities. This study provides crucial mechanistic insight into both its therapeutic and toxicological actions, establishing a translational foundation for its further development.

While not definitive, this evidence may potentially support the transcriptomic and splicing findings. SRPK1 inhibition may remodel the cervical cancer transcriptome in an HPV-linked manner, with SiHa cells exhibiting changes consistent with suppression of oncogenic signaling, whereas C33A cells adapt through translational and metabolic reprogramming.

In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumor regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treating aggressive malignancies such as high-risk neuroblastoma, exploiting the untapped polypharmacology of alectinib as an RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

Our results link replication stress, kinase signaling, and RNA processing across genetically diverse clonal states, highlighting potential therapeutic approaches at these nodes. While most splicing changes differ by splicing factor (SF) mutation, certain retained introns are common across subtypes.Changes in RI are bidirectional, concordant across mutant groups, and mirrors SRSF1 loss.SF mutations activate DDR, triggering an AMPKα/AKT imbalance that culminates in SRSF1 hypophosphorylation.Relieving R-loop induced DDR restores SRSF1 phosphorylation and reverses RI.

Well-tempered metadynamics confirmed unbinding PMF of -23.71 kcal mol-1 for CNP0199214 and -14.81 kcal mol-1 for MSC1186 (Lig_ref) to a relative difference in PMF of the screened ligand to be ≈7 kcal mol-1. A probable gating mechanism is observed for the reference ligand (Lig_ref) at the protein interface resulting multiple minima in PMF, whereas Lig_4 (CNP0199214) exhibits greater affinity toward the active pocket and therefore choice for a potent compound.

This study demonstrated that SRPK1 inhibition alters lncRNA expression and splicing-related events in PCa. These findings highlight SPHINX31's potential as a therapeutic agent, especially in combination with treatments like Olaparib, necessitating further optimization for selectivity and reduced off-target effects.

In this study, we report the design, synthesis, and preliminary biological evaluation of two hybrid molecules, geo15 and geo140, which combine known SRPK1 inhibitors with the antimetabolites gemcitabine and 5-fluorouracil (5-FU), respectively. Interestingly, treatment with geo140 did not appear to alter the overall SRPK1 distribution in interphase cells but resulted in a notable increase of mitotic cells that displayed a substantial accumulation of SRPK1, thus suggesting that the hybrid compound may have an impact on cell cycle progression. This work supports the potential of molecular hybridization as a strategy for the development of novel SRPK1-targeting anticancer agents.

It was also observed that C1orf122 significantly activated the PI3K/AKT/GSK3β signaling pathway via SRPK1. To the best of our knowledge, this is the first study to demonstrate the involvement of the C1orf122-SRPK1-PI3K/AKT/GSK3β axis in HCC growth.

As for GH-secreting primary cultures from GH-PitNETs, SRPIN340 incubation resulted in reduced VEGF165a expression (-50.6% vs control cells) and GH secretion (-14.45 (8.17)%, p < 0.05 vs control cells). In conclusion, SRPK1 inhibition may represent a novel approach to exert antitumoral effects in somatotroph tumoral cells via SRPK1-SRSF1-VEGF pathway regulation.