Henan Academy of Sciences

Lung cancer is the leading cause of cancer-related death and has the second-highest incidence worldwide. For patients with advanced EGFR-mutated non-small cell lung cancer, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment option; however, acquired resistance to TKIs is inevitable. Gefitinib and osimertinib, the first-generation and third-generation EGFR-TKI, have shown promising results in patients with EGFR-mutated lung cancer in clinical treatment. Here, we identified that pyruvate dehydrogenase kinase 1 (PDK1) was up-regulated in gefitinib- and osimertinib-resistant cell lines, and PDK1 knockdown rendered cells more sensitive to TKI treatment. PDK1 expression levels were significantly increased in lung, colon, liver, and breast cancer tissues compared with those in normal tissues. Histone demethylase KDM3A was also induced in TKI-resistant cell lines, and demethylated histone H3 lysine 9 to facilitate PDK1 expression to regulate TKI resistance. Further study demonstrated that METTL16 promoted the m6A modification of PDK1 mRNA, and the m6A reader IGF2BP1 directly recognized and enhanced PDK1 mRNA stability. Interestingly, KDM3A also induced METTL16 expression. Moreover, PDK1 inhibitor JX06 rendered cancer cells more sensitive to gefitinib treatment in vivo, and JX06 and gefitinib combination treatments have a synergic effect to inhibit tumor growth. In conclusion, the KDM3A/METTL16/PDK1 axis plays an important role in cancer development and TKI resistance, which may offer new prognostic biomarkers and therapeutic targets for TKI resistance in the future.

Catalyst supports are indispensable for efficient water dissociation since they play key roles in either indirectly enhancing catalysis activity by modifying electronic structures of catalysts or directly participating in catalytic reaction. MXene has recently emerged as a promising catalyst support for water dissociation by virtue of its rich surface electronic states that enable various electronic modifications of catalysts, but its potential of directly interacting with reactants or products to accelerate catalytic dynamics in water dissociation remains unexplored. Here we report our finding that phosphate anion-engineered MXene is capable of significantly accelerating water dissociation on single-atom ruthenium-copper (Ru-Cu) alloy, achieving a record-high mass-specific activity of 746 L gRu -1 min-1 under light conditions at room temperature. This is mainly enabled by the accelerated hydrogen spillover effect, which results from the phosphate anion-induced electronic modification of titanium sites on MXene following the light-enhanced activation of ammonia borane and water molecules on Ru-Cu active sites. This underlying mechanism is elucidated by a combination of in situ spectroscopic characterizations and density function theory calculations. This work unveils a previously unrecognized catalytic role of MXene-based supports and offers a new design strategy for enhancing water dissociation through tailored support-catalyst-reactant interactions.

Glycine, a non-essential amino acid, has been linked to improved metabolic health and enhanced insulin secretion, yet its mechanistic role in β-cell function remains poorly defined. Here, we identify a glycine-GLRA1-calmodulin signaling axis that regulates endoplasmic reticulum (ER) calcium homeostasis to support insulin biosynthesis and β-cell survival. Dietary glycine deficiency impairs insulin secretion, reduces islet mass, and worsens glucose intolerance, while overexpression of serine hydroxymethyltransferase 2 (Shmt2), a key glycine biosynthetic enzyme, increases circulating glycine, enhances insulin output, and improves glucose control. Conversely, β-cell-specific deletion of Glra1 phenocopies glycine deficiency, disrupting ER calcium dynamics, amplifying ER stress, and impairing insulin gene expression and secretion. Mechanistically, GLRA1 interacts with calmodulin to sustain ER calcium levels and alleviate ER stress, preserving β-cell viability under metabolic stress. Human genetic and transcriptomic analyses reveal that GLRA1 expression and variants are associated with insulin secretion and glycemic traits, underscoring clinical relevance. These findings establish glycine as a signaling metabolite that activates a receptor-calcium axis to maintain β-cell function, offering a mechanistic rationale for targeting GLRA1 or dietary glycine in diabetes therapy.