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

Targeting p38α promotes Parkin-mediated mitophagy to attenuate severe acute pancreatitis via suppressing the mtDNA/cGAS-STING signaling pathway

Severe acute pancreatitis (SAP) is a life-threatening acute inflammatory disorder characterized by systemic inflammation and high mortality, for which specific targeted therapeutic strategies are still severely lacking in clinical practice. Mitochondrial dysfunction and impaired mitophagy have been validated as critical pathological drivers of SAP; nevertheless, the precise molecular targets governing the dysregulation of mitochondrial quality control remain poorly defined. Herein, we identify p38α (MAPK14) as a central regulator of mitophagy during SAP progression. Combining bioinformatic screening with an experimental SAP model, we demonstrate aberrantly hyperactivated p38α in pancreatic acinar cells. Mechanistically, activated p38α phosphorylates the S131 site of the E3 ubiquitin ligase Parkin. This site-specific phosphorylation triggers a “ubiquitination switch”, which selectively accelerates K48-linked polyubiquitination-dependent degradation of Parkin while impairing its K63-linked autoubiquitination and functional activity. Consequently, blockade of Parkin-dependent mitophagy results in accumulation of damaged mitochondria and massive leakage of mitochondrial DNA (mtDNA) into the cytoplasm, which further activates the cGAS-STING signaling cascade and exacerbates the sterile inflammatory storm. Pharmacological inhibition of p38α or genetic overexpression of the phosphorylation-deficient Parkin mutant (S131A) effectively restores mitophagic flux, eliminates cytoplasmic mtDNA accumulation, and suppresses cGAS-STING-mediated pro-inflammatory cytokine release, thereby markedly alleviating pathological injury in SAP. Our study illuminates a novel role of the p38α/Parkin/mtDNA/cGAS-STING signaling axis in the pathogenesis of SAP, and highlights targeting the p38α-mediated Parkin S131 phosphorylation switch as a promising therapeutic strategy for clinical intervention against SAP.

CDK4/MERCs/PINK1 Axis Drives PFOA/HFPO‐TA‐Induced Cardiac Senescence via Mitophagy Defect and cGAS‐STING Activation: In Vitro Amelioration by Cycloastragenol

ABSTRACT Per‐ and polyfluoroalkyl substances (PFAS) are ubiquitous persistent environmental pollutants with high bioaccumulation potential and widespread human exposure risks in contaminated water, soil, and biota. Although extensive studies have established the hepatotoxic potential of PFAS, much less is known regarding their cardiotoxicity and the underlying molecular mechanisms. Here, we investigated the cardiotoxic effects and molecular pathways of two representative PFAS, perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO‐TA). Exposure to either PFOA or HFPO‑TA caused cardiac structural and functional damage, mitochondrial morphological abnormalities, and increased cardiac senescence, with HFPO‐TA eliciting greater cardiotoxicity. Mechanistically, PFOA and HFPO‐TA suppress CDK4 expression, destabilize mitochondria‐endoplasmic reticulum contacts (MERCs), and impair PINK1/Parkin‐mediated mitophagy. This defective mitophagy promotes mitochondrial DNA leakage and subsequent activation of the cGAS‐STING pathway, ultimately driving cardiac senescence. Notably, cycloastragenol (CAG) effectively reverses CDK4 downregulation, restores MERCs stability, and attenuates PFOA/HFPO‐TA‐induced cardiac senescence in vitro. Collectively, this study uncovers a CDK4/MERCs/PINK1 axis mediating PFOA/HFPO‐TA‐induced myocardial toxicity and identifies CAG as a promising natural product for mitigating environmental pollutant‐induced cardiac senescence, offering insights for PFAS health risk assessment and intervention strategies.

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

Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models.

Methyltransferase METTL1 Upregulates USF2 in a m7G-Dependent Manner to Accelerate Septic Cardiomyopathy by Inactivating PINK1/Parkin-Mediated Mitophagy

SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure

The PON1-NDUFA4 axis maintains mitochondrial respiratory fitness and drives lenvatinib tolerance in hepatocellular carcinoma.

Metabolic plasticity driven by mitochondrial oxidative phosphorylation (OXPHOS) is increasingly recognized as a key determinant of therapeutic tolerance in hepatocellular carcinoma (HCC), but the upstream regulators that preserve electron transport chain stability during treatment remain poorly defined. In this study, we identified paraoxonase-1 (PON1) as a clinically relevant regulator of mitochondrial metabolism and lenvatinib response in HCC. PON1 was markedly upregulated in HCC and independently associated with poor overall and recurrence-free survival. Functionally, PON1 promoted tumor growth and conferred robust tolerance to lenvatinib. Mechanistically, PON1 directly interacted with and stabilized NDUFA4, a key component required for complex IV assembly, thereby maintaining mitochondrial membrane potential, complex IV integrity, and OXPHOS-dependent adenosine triphosphate production while limiting reactive oxygen species accumulation. Genetic silencing of PON1 or NDUFA4 impaired mitochondrial respiration, increased oxidative stress, and restored lenvatinib sensitivity in HCC cells and xenograft models. Structure-guided virtual screening identified the Food and Drug Administration-approved CFTR corrector lumacaftor as a potent modulator of PON1 that disrupted the PON1-NDUFA4 interaction and enhanced the antitumor efficacy of lenvatinib in vivo. These findings identify the PON1-NDUFA4 axis as a previously unrecognized metabolic vulnerability that sustains mitochondrial respiratory fitness and lenvatinib resistance in HCC. Targeting mitochondrial protein-stabilizing mechanisms such as PON1-NDUFA4 may offer a broadly applicable strategy for overcoming therapy resistance in liver cancer and other aggressive malignancies. Implications: These findings establish mitochondrial protein stabilization as an actionable therapeutic vulnerability and provide a rationale for combination strategies to overcome targeted therapy resistance in HCC.