Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both non-enzymatic reactions and enzymatic mechanisms. Natural products have demonstrated potential effects on various enzymes, including GPX4, HO-1, NQO1, NOX4, GCLC, and GCLM, which are mainly involved in glutathione metabolic pathway or oxidative stress regulation, and ACSL3 and ACSL4, which mainly participate in lipid metabolism, thereby influencing the regulation of ferroptosis. In this review, we have provided a comprehensive overview of the existing literature pertaining to the effects of natural products on enzymes involved in ferroptosis and discussed their potential implications for the prevention and treatment of ferroptosis-related diseases. We also highlight the potential challenge that the majority of research has concentrated on investigating the impact of natural products on the expression of enzymes involving ferroptosis while limited attention is given to the regulation of enzyme activity. This observation underscores the considerable potential and scope for exploring the influence of natural products on enzyme activity.

Copper/zinc superoxide dismutase (SOD1) can clear cisplatin‐ (CP‐) induced excessive reactive oxygen species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell‐penetrating peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP‐SOD1 and investigating its effects on CP‐induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA‐Ni²⁺ column. In in vitro experiments, CPPs‐SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK‐2 cells. For in vivo experiments, mice were administered PSF‐SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT‐SOD1, we found that PSF‐SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF‐SOD1 inhibited CP‐induced apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP‐induced MMP loss in VERO and HK‐2 kidney cells. Treatment of mice with PSF‐SOD1 inhibited CP‐induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF‐SOD1 pretreatment. Overall, PSF‐SOD1 ameliorated CP‐induced renal damage by partially reducing oxidative stress and cell apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT‐SOD1.

Background: XueBiJing injection (XBJ) is renowned for its multi-target pharmacological effects, including immunomodulatory, antithrombotic, and antioxidant activities, offering potential therapeutic benefits for patients with severe infections such as sepsis and Coronavirus disease 2019 (COVID-19). Despite its clinical effectiveness, the molecular targets and mechanisms of XBJ remain unclear, warranting further investigation. Purpose: This study aimed to identify the key bioactive compounds in XBJ and elucidate their molecular targets and mechanisms. Methods: The zebrafish model was first used to evaluate the anti-inflammatory and antioxidant effects of XBJ, and the differentially expressed genes (DEGs) were identified by RNA sequencing and network analysis. Network pharmacology was used to analyze the relationship between bioactive compounds and molecular targets, and molecular docking and kinetic simulation were used to explore the target binding ability of key compounds. Cellular Thermal Shift Assay-Western Blot (CETSA-WB) and Surface Plasmon Resonance (SPR) further verified the interaction between compounds and targets; finally, the key pathways were confirmed by gene silencing experiments. Results: The zebrafish model results reveal that XBJ significantly reduced neutrophil and macrophage counts in a dose-dependent manner, emphasizing its potent anti-inflammatory effects. A transcriptomic analysis highlighted the differential expression of key genes in the KEAP1/NRF2 pathway, including HMOX1, SLC7A11, NQO1, and TXNRD1. A network analysis further pinpointed KEAP1 as a central molecular target, with tanshinone IIA, baicalein, and luteolin identified as key active compounds modulating this pathway. Among these, tanshinone IIA and baicalein exhibited strong binding interactions with KEAP1, which were confirmed through molecular docking and kinetic simulations. Further validation showed that baicalein directly targets KEAP1, as demonstrated by CETSA-WB and SPR analysis. Additionally, the gene silencing experiments of KEAP1 and NRF2 reinforced their crucial roles in activating the KEAP1/NRF2 pathway. Conclusion: These findings collectively establish baicalein as a critical bioactive compound in XBJ, driving its antioxidant and anti-inflammatory effects via KEAP1/NRF2 pathway activation through direct binding to KEAP1, providing new insights into the mechanism of action of XBJ.

As an agri-food by-product, the rice bran of pigmented rice, encompassing varieties such as red, black, and purple rice, has garnered increasing attention due to its richness in terms of bioactive compounds. Being mainly composed of the pericarp, aleuron, seed coat, and germ, the brown outer layer of the rice kernel offers potential health benefits and has applications in skincare. Human skin serves as the primary barrier against external threats, including pathogens, pollutants, and ultraviolet (UV) radiation. Notably, UV radiation accelerates the aging process and contributes to various skin issues. Recent trends suggest a heightened interest in incorporating pigmented rice into skincare regimens, motivated by its potential to mitigate oxidative stress, inflammation, and pigmentation, which are pivotal factors in skin aging and photodamage. With increasing consumer demand for natural and sustainable ingredients, pigmented rice has emerged as a promising candidate within the skincare and personal care sectors, effectively bridging the gap between nutrition and dermatological health. This review examines the applications of pigmented rice in skincare, with a particular focus on its bioactive components and potential mechanisms of action that contribute to skin health. The unique chemical composition of pigmented rice, which includes compounds such as anthocyanins, flavonoids, phenolic acids, and vitamin E, underlies its antioxidant, anti-inflammatory, and skin-protective properties. Despite the increasing recognition of its benefits, a comprehensive understanding of the underlying mechanisms remains limited, underscoring the necessity for further research to exploit the potential of pigmented rice in skincare applications fully.

Background/Objectives: ATPase family AAA domain-containing protein 2 (ATAD2) is an oncogenic chromatin regulator that amplifies E2F/MYC transcriptional programs, yet direct modulators remain scarce. Arecoline (ARE), the primary alkaloid of the areca nut, is a known carcinogen but paradoxically exhibits context-dependent anti-proliferative activities. In this study, we resolve this paradox by defining ARE’s anti-cancer mechanism. Methods: Breast cancer cell proliferation and colony formation assays were performed to evaluate the anti-proliferative effects of ARE. Cell-cycle distribution was analyzed to determine phase-specific effects. Transcriptomic profiling was conducted to identify affected gene networks. An unbiased Cellular Thermal Shift Assay–Mass Spectrometry (CETSA-MS) screening was used to identify direct protein targets, followed by CETSA–Western blotting for validation. Finally, in silico structure-based design was applied to generate novel derivatives with improved predicted properties. Results: ARE suppressed breast cancer cell proliferation and colony formation by inducing G1/S phase arrest. Transcriptomic analysis revealed that this phenotype was driven by profound suppression of the E2F/Cell Cycle gene network. CETSA-MS identified ATAD2 through multi-omics convergence, as the 67 direct targets were collectively most significantly enriched in the E2F pathway. CETSA–Western blotting confirmed that ARE binds and thermally stabilizes ATAD2. Mechanistically, ARE engagement of ATAD2 led to downregulation of key downstream proteins, including MYC and Cyclin D1, directly linking target modulation to G1/S arrest. Structure-based design further yielded novel derivatives with predicted enhanced ATAD2 binding and substantially reduced toxicity. Conclusions: Together, these findings uncover ATAD2 as a druggable target of ARE, establish proof-of-concept for repurposing this scaffold, and provide a rational framework for developing safer ATAD2-targeted therapies.

In response to environmental changes, bacteria have evolved sophisticated regulatory networks that incorporate small RNAs (sRNAs) and transcription factors (TFs) to fine-tune cellular physiology. Both sRNAs and TFs modulate gene expression, but the former function via post-transcriptional mechanisms, while the latter act at the transcriptional level. However, it remains unclear why both regulatory layers are conserved through evolution, rather than one being sufficient. Here, we experimentally identified that CRP, a global regulator, regulates 25 small RNAs (sRNAs) in Escherichia coli. Interestingly, CRP also controls 80% of the target genes of these sRNAs. This architecture led us to identify 34 novel sRNA-mediated feed-forward loops (sFFLs) circuits where CRP regulates both an sRNA and its target within the CRP regulon. Quantitative PCR analysis of 16 such sFFLs revealed that each type possesses a distinct cAMP dose-response profile, suggesting that different sFFL structures embody unique regulatory logic. Specifically, coherent and incoherent type 3 and 4 sFFLs exhibit broader dynamic ranges in their dose-response compared to open-loop controls. Coherent and incoherent type 1 and 2 sFFLs appear more energy-efficient. Altogether, we propose that sRNAs cooperate with TFs through sFFLs to optimize both the energy efficiency and the diversity of signal response profiles. Therefore, sRNAs serve as critical components integrating transcriptional and post-transcriptional networks across diverse cellular pathways.