A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.

6PPD is a widely used tire antioxidant that readily transforms into its more toxic ozonation product, 6PPD-quinone (6PPD-Q). Both compounds are emerging environmental contaminants with potential neurotoxic risks, yet their molecular mechanisms in Alzheimer’s disease (AD) and Parkinson’s disease (PD) remain unclear. This study integrated network toxicology, molecular docking, transcriptomic validation, and experimental models to investigate their neurotoxic effects. In silico analyses predicted significant neurotoxicity and blood–brain barrier permeability for both compounds. Target prediction and PPI network analysis identified 145/121 overlapping targets with AD/PD for 6PPD and 120/100 for 6PPD-Q. Functional enrichment analysis suggested that 6PPD-associated targets were mainly enriched in axon regeneration-, p75NTR-, and AGE-RAGE-related pathways, whereas 6PPD-Q-associated targets were enriched in MAPK cascade-, endosomal TLR signaling-, and amyloid-β formation-related pathways. Molecular docking suggested favorable binding affinities between these compounds and several core targets, including MAP2K1, EGFR, GSK3B, and CYCS. Transcriptomic validation in GEO datasets prioritized multiple hub genes. In vivo experiments showed activation of apoptosis-related signaling in the brain, while in vitro assays demonstrated ROS accumulation and neuroinflammatory activation (elevated TNF-α, IL-1β, IL-6, IFN-γ). CYCS and MAP2K1 emerged as key convergent nodes. Our findings reveal distinct yet synergistic neurotoxic mechanisms of 6PPD and 6PPD-Q in AD and PD, highlighting tire-derived pollutants as potential environmental risk factors for neurodegenerative diseases.

Ferroptosis is fairly different from other types of cell-death in biochemical processes, morphological changes and genetics as a special programmed cell-death. Here we summarize the current literatures on ferroptosis, including the cascade reaction of key material metabolism in the process, dysfunction of organelles, the relationship between different organelles and the way positive and negative key regulatory factors to affect ferroptosis in the epigenetic level. Based on material metabolism or epigenetic regulation, it is obvious that the regulatory network of ferroptosis is interrelated and complex.

6PPD and its ozonation product 6PPD-quinone (6PPD-Q) are ubiquitous tire-derived pollutants linked to environmental and potential human health risks. This study systematically investigated their mechanisms in lipid-metabolism-related diseases (atherosclerosis, type 2 diabetes, and nonalcoholic fatty liver disease) through network toxicology, transcriptomic validation, molecular docking, and experimental models. Targets of 6PPD and 6PPD-Q were predicted using multiple databases and intersected with disease-associated genes. Protein–protein interaction networks, hub gene screening, GO/KEGG enrichment, and GEO transcriptomic datasets identified key shared core targets, including PTGS2, MMP9, CXCL8 (for 6PPD), MAPK14, and PTGS2 (for 6PPD-Q). Molecular docking suggested potential strong binding affinities. Integrative analysis highlighted convergence on oxidative stress, inflammation, lipid dysregulation, and MAPK signaling. In vivo, 40-day exposure to 6PPD and 6PPD-Q in C57BL/6 mice induced hepatic steatosis, elevated serum TC, LDL-C, and HDL-C, upregulated inflammatory cytokines (TNF-α, IL1B, IL6, and IFNG), and core targets. In vitro, both compounds caused dose-dependent cytotoxicity, ROS accumulation, glutathione redox imbalance, and pro-inflammatory activation. These findings suggest that 6PPD and 6PPD-Q may contribute to lipid-metabolism-related toxic responses through shared and distinct processes involving oxidative stress, inflammatory activation, and lipid dysregulation. These results provide preliminary mechanistic insights into their metabolic toxicity and support further experimental evaluation for environmental health risk assessment.