Free Radical Biology and Medicine最新文献

Cannabigerol (CBG), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention owing to its antibiotic, anti-inflammatory, and anticancer properties. However, its therapeutic potential in pancreatic cancer remains unknown. In this study, we demonstrated for the first time that CBG exerts a potent antiproliferative effect on human pancreatic cancer cells by inducing cell cycle arrest in the G₁ phase and promoting programmed cell death. Transcriptomic profiling revealed that CBG significantly modulates the gene networks involved in apoptosis and ferroptosis. Consistent with these findings, CBG treatment upregulated apoptosis-associated proteins, such as cleaved caspase-3, caspase-9, and PARP1, and increased the proportion of apoptotic cells. CBG triggered robust activation of the unfolded protein response (UPR), with a marked increase in the transcriptional levels of endoplasmic reticulum (ER) stress-related genes. Mechanistically, CBG activated the IRE1α-XBP1 axis, a key branch of the UPR, as evidenced by enhanced XBP1 mRNA splicing. Inhibition of IRE1α by the small-molecule inhibitor 4μ8C substantially mitigated CBG-induced cytotoxicity, emphasizing the central role of ER stress pathways in the mechanism of CBG's action. Moreover, CBG modulated the expression of ferroptosis-related genes and proteins, such as DDIT3, NFE2L2, and HMOX1, and their respective protein products, CHOP, NRF2, and HO-1. These findings reveal a novel mechanism by which CBG concurrently induces apoptosis and ferroptosis via ER stress-driven activation of the IRE1α pathway, supporting its potential as a therapeutic agent targeting ER stress-related vulnerabilities in pancreatic cancer.

Humanin is a mitochondrial-derived peptide with cytoprotective properties, but how it has evolved in response to different oxidative stress levels in mammals is not fully understood. This study examines how Humanin sequences have adapted to species-specific metabolic and environmental pressures. We compared the peptide in several mammalian species categorized by their distinct oxidative stress profiles: small mammals such as shrews with high metabolic rates and elevated endogenous ROS production, cetaceans exposed to hypoxia-reoxygenation cycles during deep diving, and long-lived primates facing cumulative oxidative stress over extended lifespans. Using bioinformatic tools, we analyzed physicochemical traits such as structural stability, the aliphatic index, and oxidation susceptibility. We also used protein-protein docking to estimate binding affinities between Humanin variants and key ligands like BAX and FPRL1. Our results show that Humanin is not a static molecule. Species facing high oxidative stress, such as cetaceans and bats, possess variants that are more stable and chemically robust. In contrast, species with high ROS production but lower antioxidant capacity, like the shrew, have less robust versions of the peptide. Simulation data indicate that variants from mammals living in extreme conditions maintain or improve interactions with proteins involved in cell survival. These findings suggest that evolution has tuned Humanin to optimize mitochondrial protection across different physiological contexts. These natural isoforms provide a structural basis for designing new therapeutic analogs to treat oxidative stress-related diseases in humans.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in elderly people, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles, resulting in neurodegeneration and cognitive decline. Emerging evidence identifies PANoptosis, a lytic form of programmed cell death that integrates pyroptosis, apoptosis and necroptosis as a central driver of AD progression. PANoptosis is orchestrated by multiprotein PANoptosome complexes such as RIPK1, AIM2, ZBP1 and NLRP12, which are activated by caspases, receptor- interacting protein kinases and innate immune stimuli including pathogen associated molecular pattern and damage associated molecular pattern. In AD, Aβ and tau aggregates activate inflammasomes, trigger mitochondrial dysfunction associated oxidative stress, and provoke chronic neuroinflammation, resulting in sustained PANoptotic cell death. Dysregulation of signalling pathways, including cGAS-STING, PI3K/ AKT, JAK/STAT/IRF1, and p38/ERK/JNK MAPK contribute to PANoptosis by enhancing inflammation, free radical generation, mitochondrial damage, synaptic impairment, and BBB disruption. Preclinical studies on compounds like celasterol, magnoflorin, calycosin, and liproxstatin-1, along with clinical trials on the drugs including nicotinamide riboside, barcitinib, dexmeditomidine, and semaglutide, suggest a neuroprotective potential by modulating PANoptotic pathways. This review underscores PANoptosis as a critical pathological mechanism in AD and highlights novel therapeutic avenues aimed at disrupting this cell death program to mitigate AD progression.

The mitochondria-associated endoplasmic reticulum membrane (MAM) is crucial for mitochondrial homeostasis. Excessive mitochondrial fission has been recognized as an early pathological event in podocyte injury in diabetic kidney disease (DKD). Cyclase-associated protein 1 (CAP1), an actin-binding protein, has been implicated as a potential regulator of mitochondrial dynamics; however, its role in DKD remains unclear. This study revealed that increased MAM formation is associated with excessive mitochondrial fission in podocytes from DKD patients. Podocyte-specific CAP1 knockdown significantly ameliorated podocyte injury and albuminuria in diabetic mice, with the protective effect attributed to the inhibition of MAM formation and mitochondrial fission. Mechanistically, high glucose triggered the CAP1-induced actin depolymerization, which promoted the enrichment of inverted formin 2 (INF2) from the endoplasmic reticulum (ER) to the MAM. At the MAM interface, the protein interaction between CAP1 and the enriched INF2 was enhanced, thereby exacerbating mitochondrial fission and dysfunction, which ultimately led to podocyte injury. Our findings not only provide the first evidence for the pathogenic role of CAP1 in podocytes during DKD progression, but also elucidate a novel mechanism by which CAP1 modulates mitochondrial fission via the MAM.

Epidermal growth factor receptor (EGFR) is overexpressed in most triple-negative breast cancer (TNBC) patients with poor prognosis; however, the therapeutic benefit of EGFR inhibitors (EGFRi) in breast cancer remains limited. In this study, we found poor response to EGFRi in TNBC was related to oxidative phosphorylation (OXPHOS) and breast cancer stem cells (BCSCs), and demonstrated that TDP43 (TAR DNA-binding protein 43) expression is positively correlated with non-response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). TDP43 knockdown significantly enhances EGFR-TKI sensitivity and decreases EGFR-TKI resistance. Mechanistically, TDP43, a DNA/RNA-binding protein predominantly localized to the nucleus, translocates to mitochondria upon EGFR-TKI stimulation. The increased mitochondrial localization promotes OXPHOS, thereby enriching BCSCs and contributing to EGFR-TKI resistance. Inhibiting TDP43 expression or using our newly identified TDP43 inhibitor, atovaquone, suppresses OXPHOS and reduces EGFR-TKI resistance. Overall, our research identified TDP43 as a key regulator of EGFR-TKI sensitivity and resistance, and offers new therapeutic targets and promising application perspectives in TNBC.