Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma

PGAM5-mediated VDAC1 oligomerization Facilitates Ponatinib-Induced Cardiotoxicity via Disrupting the Mitophagy-Mitochondrial unfolded protein response Synergistic Defense Crosstalk.

OBJECTIVES Ponatinib is an effective tyrosine kinase inhibitor for chronic myeloid leukemia with the T315I mutation, but its clinical use is often limited by serious cardiovascular toxicity. Although mitochondrial dysfunction has been implicated in this process, the upstream stress-sensing mechanism that converts ponatinib exposure into collapse of mitochondrial quality control (MQC) remains poorly defined. We therefore investigated whether the PGAM5/VDAC1 axis mediates ponatinib-induced cardiac injury by coordinately disrupting mitophagy and the mitochondrial unfolded protein response (UPRmt). METHODS Cardiomyocyte-specific PGAM5 knockout mice (Pgam5_cko) and littermate controls (Pgam5_f/f) were fed a high-fat diet and then exposed to ponatinib. Cardiac function and adult cardiomyocyte contractility were assessed by echocardiography and IonOptix analysis. Single-cell RNA sequencing, in vivo genetic loss-of-function models, and HL-1 cells with stable Pgam5 knockdown were used to define the underlying mechanism. MQC status, including mitophagy and UPRmt, was evaluated by fluorescence imaging, RT-qPCR, western blotting, and biochemical assays. RESULTS Ponatinib markedly increased PGAM5 expression in the heart and induced contractile dysfunction, inflammatory activation, and cardiomyocyte apoptosis. These changes were substantially attenuated in Pgam5_cko mice. Mechanistically, ponatinib promoted pathological oligomerization of the outer mitochondrial membrane protein VDAC1 in a PGAM5-dependent manner. This event was accompanied by simultaneous suppression of PINK1/Parkin-related mitophagy and the UPRmt program, resulting in mitochondrial fragmentation, oxidative stress, and impaired bioenergetic function. At the functional level, loss of PGAM5 restored MQC and preserved cardiac performance under ponatinib stress. Importantly, forced VDAC1 oligomerization with arsenic trioxide largely abolished the protective effects of PGAM5 deficiency, supporting VDAC1 oligomerization as a critical downstream event in this pathway. CONCLUSION These findings identify the PGAM5/VDAC1 axis as a key mechanism linking ponatinib stress to coordinated failure of MQC in the heart. By simultaneously disabling mitophagy and UPRmt, this pathway drives mitochondrial dysfunction and cardiac injury. Targeting PGAM5-dependent VDAC1 oligomerization may therefore represent a potential strategy for limiting ponatinib-associated cardiotoxicity.

Abstract A025: Dual NR4A1/2 ligands inhibit PAX3-FOXO1 and promote ferroptosis in Rhabdomyosarcoma

Targeting NR4A1/2 may represent a promising therapeutic strategy for overcoming resistance in rhabdomyosarcoma, and early CD71 induction combined with suppression of GPX4, SLC7A11, and FSP1 highlights a multi-level ferroptotic mechanism in RMS.

miR-27b-3p Exacerbates VCD-Induced KGN Cell Injury by Targeting PAPPA to Suppress IGF-1 Release and Inhibit the PI3K/AKT Pathway

A novel pathogenic mechanism whereby miR-27b-3p exacerbates VCD-induced granulosa cell injury by directly targeting PAPPA, suppressing IGF-1 release, and consequently inhibiting the PI3K/AKT pro-survival signaling pathway is uncovered.

Dual knockdown of Scn1b and Gsdmd induces an M2-like functional state in macrophages and modulates inflammation and fibrosis in a rat model of acute respiratory distress syndrome

PNPT1-induced mitochondrial dysfunction drives osteoclast activation via post-transcriptional Nrf2 suppression and lipid peroxidation signaling.

By inciting mitochondrial damage, provoking ROS buildup, and decoupling the protective autophagy-Nrf2/xCT axis, PNPT1 promotes osteoclastogenesis, thereby introducing a promising immunopharmacological target for restraining pathological bone resorption.

ATP6AP2 dysregulation as a central hub in DMD pathogenesis: An integrated multi-omics and therapeutic study.

It is demonstrated that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.