Academic Paper

AbstractOxidation reactions are fundamental transformations in organic synthesis and chemical industry. With oxygen or air as terminal oxidant, aerobic oxidation catalysis provides the most sustainable and economic oxidation processes. Most aerobic oxidation catalysis employs redox metal as its active center. While nature provides non-redox metal strategy as in pyrroloquinoline quinone (PQQ)-dependent methanol dehydrogenases (MDH), such an effective chemical version is unknown. Inspired by the recently discovered rare earth metal-dependent enzyme Ln-MDH, here we show that an open-shell semi-quinone anionic radical species in complexing with lanthanum could serve as a very efficient aerobic oxidation catalyst under ambient conditions. In this catalyst, the lanthanum(III) ion serves only as a Lewis acid promoter and the redox process occurs exclusively on the semiquinone ligand. The catalysis is initiated by 1e--reduction of lanthanum-activated ortho-quinone to a semiquinone-lanthanum complex La(SQ-.)2, which undergoes a coupled O-H/C-H (PCHT: proton coupled hydride transfer) dehydrogenation for aerobic oxidation of alcohols with up to 330 h−1 TOF.

AbstractBackgroundAdaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl‐CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self‐sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression.MethodsThe potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer‐resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In‐situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA‐sequencing employed for the mechanism verification.ResultsAfter integration of the RNA‐protein‐metabolite levels, the data revealed that a reprogramming from SCD‐dependent to FADS2‐dependent desaturation was linked to cancer epithelial‐mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β‐catenin self‐reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate‐activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor‐β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT.ConclusionsThese findings revealed a metabolic reprogramming from SCD‐dependent to FADS2‐dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.

AbstractGlycosphingolipids (GSLs) are essential components of cell membranes, particularly enriched in the nervous system. Altered molecular distributions of GSLs are increasingly associated with human diseases, emphasizing the significance of lipidomic profiling. Traditional GSL analysis methods are hampered by matrix effect from phospholipids and the difficulty in distinguishing structural isomers. Herein, we introduce a highly sensitive workflow that harnesses magnetic TiO2 nanoparticle-based selective enrichment, charge-tagging Paternò–Büchi reaction, and liquid chromatography-tandem mass spectrometry. This approach enables mapping over 300 distinct GSLs in brain tissues by defining sugar types, long chain bases, N-acyl chains, and the locations of desaturation and hydroxylation. Relative quantitation of GSLs across multiple structural levels provides evidence of dysregulated gene and protein expressions of FA2H and CerS2 in human glioma tissue. Based on the structural features of GSLs, our method accurately differentiates human glioma with/without isocitrate dehydrogenase genetic mutation, and normal brain tissue.