Zhuoran Zhang | PubMed Health

PubMed2026

Alternative oxidase pathway inhibits PuWRKY7-PuHDAC15 complex to promote ester aroma synthesis in Nanguo pear.

Volatile esters are key contributors to the characteristic aroma in fruit, and their accumulation directly dictates fruit quality and consumer acceptance. The alternative oxidase pathway is known for its role in regulating fruit quality, but its molecular mechanism in ester aroma accumulation remains unclear. Here, we demonstrated that the alternative oxidase pathway acts as the dominant respiratory pathway in Nanguo pear (Pyrus ussuriensis) during ripening and promotes ester aroma accumulation by increasing histone acetylation levels of PuAAT1 (alcohol acetyltransferase 1), the key gene governing ester synthesis. Further, we identified PuHDAC15 as a critical histone deacetylase that modulates acetylation levels and interacts with the transcription factor PuWRKY7. Mechanistically, PuWRKY7 directly binds to the W-box elements in the PuAAT1 promoter. The PuHDAC15-PuWRKY7 complex acts synergistically to repress PuAAT1 transcription, thereby decreasing its histone acetylation levels and gene expression, and consequently inhibiting ester aroma accumulation in Nanguo pear. This study reveals how the alternative oxidase pathway integrates into fruit aroma formation via epigenetic regulation and gene expression, thereby providing a scientific basis for targeted improvement of fruit quality.

Plant Proteins↗

PubMed2025

Gain-of-function PPM1D mutations attenuate ischemic stroke.

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d-/-) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d-/- mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke. Gain-of-function PPM1D mutations attenuate ischemic cerebral injury. Whole-genome sequencing data of 10,241 ischemic stroke patients from the Third Chinese National Stroke Registry (CNSR-III) identified eight patients with gain-of-function mutations in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene (17q23.2). These mutation carriers displayed improved peripheral inflammation, decreased fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Ppm1d-deficient (Ppm1d-/-) mice exhibited exacerbated stroke outcomes, characterized by enlarged infarct volumes, disrupted cerebrovascular architecture, and enhanced neuro-inflammation. Mechanistically, Ppm1d deficiency induced the disturbance of endothelial fatty acid metabolism involving the PPARα pathway. Through integrated computational modeling, virtual screening, and in vitro validation, T2755 was identified as a small molecule PPM1D stabilizer. Pharmacological PPM1D stabilization with T2755 significantly attenuated ischemic brain injury in murine models.

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