Triptolide exhibits promising efficacy in various cancers and immune diseases while its clinical application has been strongly restricted by its severe side effects, especially cardiotoxicity. However, the underlying mechanism of triptolide‐induced cardiotoxicity (TIC) remains unclear. The RNA‐seq analysis of triptolide‐injured AC16 human cardiomyocyte cell line hinted that ferroptosis is involved in TIC. Further experimental validations proved that triptolide triggered ferroptosis, as evidenced by significant accumulation of lipid peroxidation (4‐HNE and MDA levels) and ferrous iron, as well as depletion of intracellular GSH. Furthermore, triptolide‐induced iron overload involved the upregulation of TF/TRFC/DMT1 signal axis and the degradation of ferritin, which contribute to ROS generation via Fenton reaction. In addition, inhibition of the antioxidant Nrf2/HO‐1 pathway was observed in TIC, which may also lead to the overproduction of lethal lipid peroxides. Mechanistically, using streptavidin–biotin affinity pull‐down assay and computational molecular docking, we unveiled that triptolide directly binds to SLC7A11 to inactivate SLC7A11/GPX4 signal axis. More importantly, employment of a ferroptosis inhibitor Ferrostatin‐1 alleviated TIC by partially reversing the inhibitory effects of triptolide on SLC7A11/GPX4 signal. Altogether, our study demonstrated that SLC7A11/GPX4 inactivation‐mediated ferroptosis contributed to the pathogenesis of TIC. Combating ferroptosis may be a promising therapeutic avenue to prevent TIC.

Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.

Radiation-induced skin injury is a significant adverse reaction to radiotherapy. However, there is a lack of effective prevention and treatment methods for this complication. Ferulic acid (FA) has been identified as an effective anti-radiation agent. Conventional administrations of FA limit the reaching of it on skin. We aimed to develop a novel FA hydrogel to facilitate the use of FA in radiation-induced skin injury. We cross-linked carbomer 940, a commonly used adjuvant, with FA at concentrations of 5%, 10%, and 15%. Sweep source optical coherence tomography system, a novel skin structure evaluation method, was applied to investigate the influence of FA on radiation-induced skin injury. Calcein-AM/PI staining, CCK8 assay, hemolysis test and scratch test were performed to investigate the biocompatibility of FA hydrogel. The reducibility of DPPH and ABTS radicals by FA hydrogel was also performed. HE staining, Masson staining, laser Doppler blood flow monitor, and OCT imaging system are used to evaluate the degree of skin tissue damage. Potential differentially expressed genes were screened via transcriptome analysis. Good biocompatibility and in vitro antioxidant ability of the FA hydrogels were observed. 10% FA hydrogel presented a better mechanical stability than 5% and 15% FA hydrogel. All three concentrations of FA remarkably promoted the recovery of radiation-induced skin injury by reducing inflammation, oxidative conidiation, skin blood flow, and accelerating skin tissue reconstruction, collagen deposition. FA hydrogel greatly inhibiting the levels of NLRP3, caspase-1, IL-18, pro-IL-1β and IL-1β in vivo and vitro levels through restraining the activation of NLRP3 inflammasome. Transcriptome analysis indicated that FA might regulate wound healing via targeting immune response, inflammatory response, cell migration, angiogenesis, hypoxia response, and cell matrix adhesion. These findings suggest that the novel FA hydrogel is a promising therapeutic method for the prevention and treatment of radiation-induced skin injury patients.

The nephrotoxicity of Fructus Psoraleae, an effective traditional Chinese medicine for vitiligo treatment, has been reported. As one of the main toxic components in Fructus Psoraleae, bavachin (BV) was considered to be related to Fructus Psoraleae-caused adverse outcomes, but the direct evidence and molecular mechanism underlying BV-induced nephrotoxicity are not well elucidated. Therefore, this study was designed to confirm whether BV would cause toxic effects on the kidney and explore the possible mode of action. Our results demonstrated that days’ treatment with 0.5 μM BV indeed caused obvious renal fibrosis in the zebrafish kidney. The obvious E- to N-cadherin switch and the expressions of proteins promoting epithelial–mesenchymal transition (EMT) were observed in BV-treated human renal tubular epithelial and zebrafish kidneys. In addition, elevated reactive oxygen species (ROS) levels and Bip/eIF2α/CHOP-mediated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were caused by BV, both of which could be reversed by ROS scavenger N-acetyl-L-cysteine (NAC). Also, blocking ER stress-caused cytoplasmic Ca²⁺ overload with 4-PBA notably alleviated BV-induced alterations in key molecular events related to EMT and renal fibrosis. Furthermore, of the natural compounds subjected to screening, ginsenoside Rb1 significantly downregulated BV-induced ER stress by inhibiting ROS generation and following the activation of Bip/eIF2α/CHOP signaling in HK2 cells. Subsequently, BV-triggered EMT and renal fibrosis were both ameliorated by ginsenoside Rb1. In summary, our findings suggested that BV-induced ROS promoted the appearance of EMT and renal fibrosis mainly via Bip/eIF2α/CHOP-mediated ER stress. This ER stress-related toxic pathway might be a potential intervention target for BV-caused renal fibrosis, and ginsenoside Rb1 would be a promising drug against BV- or Fructus Psoraleae-induced nephrotoxicity.

Background: Acute mountain sickness (AMS) is a self-limiting illness, involving a complex series of physiological responses to rapid ascent to high altitudes, where the body is exposed to lower oxygen levels (hypoxia) and changes in atmospheric pressure. AMS is the mildest and most common form of altitude sickness; however, without adequate preparation and adherence to ascent guidelines, it can progress to life-threatening conditions. Aims: Due to the multi-factorial predisposition of AMS among individuals, identifying AMS biomarkers before high altitude exposure from multiple dimensions (e.g., clinical, metabolic, and proteomic markers) and integrating them to build an AMS predictive model enables early diagnosis and personalized interventions, which allows targeted allocation of medical resources, such as prophylactic medications (e.g., acetazolamide) and supplemental oxygen, to those who need them most and prevention of unnecessary complications. Consequently, predicting AMS utilizing biomarkers from multidimensional phenotypic data before high-altitude exposure is essential for the paradigm change in high-altitude medical research from currently applied reactive services to the cost-effective predictive, preventive, and personalized medicine (PPPM/3PM) in primary (reversible damage to health and targeted protection against health-to-disease transition) and secondary (personalized protection against disease progression) care. Methods: To this end, this study recruited 83 Han Chinese male volunteers and obtained clinical, proteomic, and metabolomic profiles for analysis before they ascended to high altitudes. The Mann–Whitney U test was used to identify clinical features distinguishing AMS from non-AMS. The proteomic and metabolomic features were concatenated and clustered to find co-expression modules associated with AMS. A machine learning model, Mutual Information-radial kernel-based Support Vector Machine-Recursive Feature Elimination (MI-radialSVM-RFE) was employed for biomarkers selection and AMS prediction. A molecular docking technique was used to select molecular biomarkers that can bind with Traditional Chinese Medicine (TCM) ingredients. Results: Among 83 participants, 66 were selected for detailed analysis after quality control steps. Six protein-metabolite co-expression modules were identified as significantly associated with AMS. The MI-radialSVM-RFE model selected 12 biomarkers (two clinical features: systolic blood pressure (SBP) and peak expiratory flow (PEF); six proteins: Acyl-CoA synthetase long-chain family member 4 (ACSL4), immunoglobulin kappa variable 1D-16 (IGKV1D-16), coagulation factor XIII B subunit (F13B), prosaposin (PSAP), poliovirus receptor (PVR), and multimerin-2 (MMRN2); and four metabolites: 2-Methyl-1,3-cyclohexadiene, calcitriol, 4-Acetamido-2-amino-6-nitrotoluene, and 20-Hydroxy-PGE2) for the AMS prediction model. The model exhibited excellent predictive performance in both training (n = 66) and validating cohorts (n = 24) with AUCs of 0.97 and 0.94, respectively. Additionally, molecular docking analysis suggested PSAP and ACSL4 proteins as potential molecular targets for AMS prevention. Conclusion and expert recommendations: This study advances high-altitude medicine by developing a predictive model for AMS using clinical, proteomic, and metabolomic data. The identified biomarkers linked to energy metabolism, immune response, and vascular regulation offer insights into AMS mechanisms. High-altitude predictive approaches should focus on implementing biomarker-driven risk screening using clinical, proteomic, and metabolomic data to identify high-risk individuals before high-altitude exposure. Preventive measures should prioritize pre-acclimatization protocols, tailored nutritional strategies and interventions guided by biomarker profiles, and lifestyle adjustments, such as maintaining mitochondrial health through proper nutritional strategies.