GSK-690693

Hepatic VLDL overproduction, tightly modulated by insulin signaling, plays a pivotal role in the progression of atherosclerosis (AS). The present study aimed to investigate whether inhibition of hepatic VLDL overproduction is a novel therapeutic strategy for the homogeneous tea polysaccharide (TPS3A) to ameliorate AS under insulin resistance (IR) conditions and the potential molecular basis involved. Results showed that TPS3A supplementation effectively alleviated systemic IR and delayed atherosclerotic plaque progression in HFD-exposed ApoE^-/- mice. Additionally, TPS3A markedly down-regulated the expression of TG synthesis markers (SREBP-1, ACC1, and FAS) and apoB lipidation markers (apoB, apoCIII, and MTP), while up-regulating the expression of apoB degradation maker (sortilin) and VLDL clearance maker (LDLR), thereby inhibiting VLDL overproduction in insulin-resistant ApoE^-/- mice and HepG2 cells. The IRS-mediated PI3K-AKT-mTORC1/FoxO1 insulin signaling cascades are central pathways regulating VLDL production. We found that TPS3A significantly abolished insulin-induced activation of PI3K, AKT, mTORC1, and nuclear FoxO1 in vivo and in vitro. Moreover, the suppression effects of TPS3A on VLDL overproduction were synergistically strengthened by inhibitors targeting PI3K (Wortmannin), AKT (GSK690693), mTORC1 (Rapamycin), and FoxO1 (AS1842856). Overall, TPS3A holds promise in ameliorating AS by inhibiting hepatic VLDL overproduction through the IRS-mediated PI3K-AKT-mTORC1/FoxO1 insulin signaling pathways.

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.