Biomedical subjects

Weidong Wu

Publications and source records attributed to Weidong Wu.

3 recordsLinked to original sources

PubMed2026

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context. MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms. KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription. SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Ferroptosis↗

PubMed2026

Comparative analysis of olfactory receptor repertoires reveals evolutionary dynamics and high-altitude adaptation in Schizopygopsis younghusbandi based on the chromosome-level genomes.

The olfactory receptor (OR) gene represent a significant multigene family in vertebrates, forming the core molecular basis of olfactory perception and playing a crucial role in the environmental adaptation of species. High-altitude ecosystems represent extreme habitats characterized by specific abiotic stresses, including low oxygen levels, low temperatures, and intense ultraviolet radiation. These environments also exhibit low aquatic biodiversity and a limited variety of odor molecules, factors that have influenced the adaptive evolution of the sensory systems in endemic species. However, the genetic mechanisms underlying olfactory adaptation in high-altitude freshwater fish remained inadequately understood. In this study, we performed comparative genomics analyses to reveal the evolutionary processes underlying the adaptive and functional evolution of OR genes in S. younghusbandi, a cyprinid fish endemic to the Qinghai-Xizang Plateau. The results indicated that, compared to their low-altitude relatives, S. younghusbandi possessed a significantly smaller number of OR genes, with only 98 genes, which revealed the contraction of the gene family. Phylogenetic analysis revealed that the OR genes of cyprinid fish could be categorized into two major lineages: type I and type II. The η and δ families, which perceive water-soluble odors, in S. younghusbandi underwent significant and specific expansion, while the ε family was completely absent. This pattern reflected adaptive changes in olfactory recognition to accommodate the simplified odor spectrum of high-altitude water bodies. Chromosomal localization analysis demonstrated that OR genes were clustered, and collinearity analysis confirmed the presence of conserved genomic fragments among species. Selection pressure analysis revealed that the Ka/Ks values of all homologous gene pairs were less than 1, indicating that the OR genes of S. younghusbandi underwent strong purifying selection as a group to preserve core olfactory function. A few genes exhibited relaxed selection characteristics, which may have facilitated the fine-tuning of adaptability to high-altitude environments. In conclusion, this study elucidated the evolutionary dynamics and adaptive characteristics of the OR gene in S. younghusbandi, offering a new perspective on the molecular mechanisms underlying olfactory adaptation at high altitudes and enriching the research on sensory evolution in vertebrates.

Schizopygopsis younghusbandi↗

PubMed2026

cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.

Endogenous cytoplasmic DNA (cytoDNA) is increasingly recognized as a mediator of tissue dysfunction and disease progression during aging. As a major cytosolic DNA-sensing pathway, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can translate aging-associated cytoDNA accumulation into innate immune and inflammatory programs. This review summarizes the evolutionary and signaling features of the cGAS-STING cascade and critically discusses its crosstalk with aging-associated intracellular molecular threats, including nuclear genomic and chromatin stress, mitochondrial dysfunction, oxidative-metabolic stress, and defective clearance of nucleic acids or damaged organelles. We further synthesize evidence linking dysregulated cGAS-STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs. Finally, we discuss the therapeutic potential and limitations of cGAS-STING modulation, emphasizing that successful translation will require context-defined therapeutic windows, tissue- and cell-specific targeting, subcellular compartmentalization, and long-term safety assessment.

Humans↗