BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury. METHODS: The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell–derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography–tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2. RESULTS: Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the CaMKII (Ca ²⁺ /calmodulin dependent protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury. CONCLUSIONS: Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.

Cancer cells frequently reprogram one-carbon metabolic pathways to fulfill their vigorous demands of biosynthesis and antioxidant defense for survival and proliferation. Dysfunction of oncogenes or tumor suppressor genes is critically involved in this process, but the precise mechanisms by which cancer cells actively trigger one-carbon metabolic alterations remain incompletely elucidated. Here, by using untargeted metabolomic analysis, we identify the oncoprotein SE translocation (SET) as a key regulator of one-carbon metabolism in cancer cells. SET physically interacts with mitochondrial SHMT2 and facilitates SHMT2 enzymatic activity. Loss of SET profoundly suppresses serine-derived one-carbon metabolic flux, whereas reexpression of ectopic SET leads to the opposite effect. Notably, although the presence of SHMT2 is critical for SET-mediated one-carbon metabolic alterations, the depletion of SHMT2 alone is insufficient to antagonize SET-induced tumor growth, probably due to functional compensation by its cytosolic isozyme SHMT1 upon SHMT2 knockdown. Instead, pharmacological targeting of cellular SHMT (including both SHMT1 and SHMT2) activity results in dramatic suppression of SET-induced tumor growth. Moreover, by using a Kras/Lkb1 mutation-driven lung tumor mouse model, we demonstrate that the loss of SET compromises both tumor formation and intratumoral SHMT2 enzymatic activity. Clinically, the overexpression of SET and SHMT2 is observed in lung tumors, both of which correlate with poor prognosis. Our study reveals a SET–SHMT2 axis in regulating serine-derived one-carbon metabolism and uncovers one-carbon metabolic reprogramming as a mechanism for SET-driven tumorigenesis.

Aspergillus cristatus is a key microorganism involved in the fermentation of Fu brick tea, but systematic strain-level safety data remain limited despite its long history of use in dark tea production. In this study, the toxicological safety of A. cristatus CCNH008 was assessed through acute oral toxicity assay, a 90-day repeated oral toxicity study with a recovery period and genotoxicity assays. In acute oral toxicity tests, CCNH008 caused no mortality, no adverse clinical signs, and no treatment-related effects on bodyweight or pathology in mice or rats, with an LD₅₀ greater than 10 g/kg bodyweight. In the 90-day repeated oral toxicity study in rats, the oral administration of CCNH008 at doses up to 1.67 g/kg bodyweight/day produced no treatment-related changes in clinical signs, bodyweight, food consumption, hematological or biochemical parameters, urinalysis, organ weights, or histopathology, including during a 28-day recovery period. Genotoxicity was evaluated using a bacterial reverse mutation assay, an in vitro mammalian chromosome aberration test, and an in vivo mammalian erythrocyte micronucleus test; no mutagenic or clastogenic effects were observed. Collectively, these findings demonstrate that CCNH008 shows no evidence of acute, subchronic oral toxicity, or genotoxicity, providing important strain-level safety evidence to support its potential application in food-related products.

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