Non-alcoholic fatty liver disease (NAFLD) is common chronic metabolic liver disorder which is associated with fat accumulation in the liver. It causes a wide range of pathological effects such as insulin resistance, obesity, hypertension, diabetes, non-alcoholic steatohepatitis (NASH) and cirrhosis, cardiovascular diseases. The molecular mechanisms that cause the initiation and progression of NAFLD remain fully unclear. Inflammation is regarded as a significant mechanism which could result in cell death and tissue injury. Accumulation of leukocytes and hepatic inflammation are important contributors in NAFLD. Excessive inflammatory response can deteriorate the tissue injury in NAFLD. Thus, inhibition of inflammation improves NAFLD by reducing intrahepatic fat content, increasing β-oxidation of fatty acids, inducing hepato-protective autophagy, overexpressing peroxisome proliferator-activated receptor- γ (PPAR-γ), as well as attenuating hepatocyte apoptosis and increasing insulin sensitivity. Therefore, understanding the molecules and signaling pathways suggests us valuable information about NAFLD progression. This review aimed to evaluate the inflammation in NAFLD and the molecular mechanism on NAFLD.

Copper is an important mineral, and moderate copper is required to maintain physiological processes in nervous system including cerebral ischemia/reperfusion (I/R) injury. Over the past few decades, copper induced cell death, named cuprotosis, has attracted increasing attention. Several lines of evidence have confirmed cuprotosis exerts pivotal role in diverse of pathological processes, such as cancer, neurodegenerative diseases, and I/R injury. Therefore, an in-depth understanding of the interaction mechanism between copper-mediated cell death and I/R injury may reveal the significant alterations about cellular copper-mediated homeostasis in physiological and pathophysiological conditions, as well as therapeutic strategies deciphering copper-induced cell death in cerebral I/R injury.

Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, critically contributes to cerebral ischemia/reperfusion (I/R) injury. In ischemic stroke, neuronal ferroptosis arises from iron overload and antioxidant system failure. Excessive Fe²⁺ fuels hydroxyl radical production via the Fenton reaction, accelerating lipid peroxidation in PUFA-rich membranes. Concurrently, cysteine depletion and GPX4 inactivation disrupt the GPX4-glutathione antioxidant axis, allowing toxic lipid peroxide accumulation. Enzymes like ACSL4 and LPCAT3 esterify PUFAs into phospholipids, enabling lipoxygenases (LOXs) to generate peroxides, while impaired repair pathways (eg, FSP1-CoQ10) exacerbate damage. Therapeutic strategies target iron chelators (eg, deferoxamine), lipid peroxidation inhibitors (liproxstatin-1), and GPX4 activators to restore redox balance. Targeting propagation mediators (eg, Galectin-13, which reduces SLC7A11 membrane localization) may limit damage spread. Combinatorial therapies addressing iron regulation and lipid peroxidation pathways offer promising neuroprotection against I/R-related neurodegeneration, positioning ferroptosis as a key druggable target.

Even with reperfusion therapy, ischemia-reperfusion (I/R) injury remains to be a major driver of organ failure associated with myocardial infarction, stroke, and liver transplantation, with effective therapeutic targets still elusive. Using in vitro hypoxia/reoxygenation (H/R) models, we discovered that the pharmacological inhibition of 15-lipoxygenase (ALOX15) by thiolox effectively mitigates myocardial I/R injury. While ALOX15—a well-established promoter of lipid peroxidation and ferroptosis—has been extensively studied in cardiac I/R, its involvement in multi-organ I/R injury and non-ferroptotic cell death has not been thoroughly investigated. To address this, we employed I/R models in three vital organs and found that either global deletion of Alox15 or its specific loss in hematopoietic cells (Alox15 ^ΔH ) consistently led to a reduction in infarct volume and improvement in function across the heart, brain, and liver. Mechanistically, this protection arose from the inhibition of pyroptosis. The underlying cascade involves mitochondrial reactive oxygen species (ROS) activating ALOX15 during reperfusion, which produces 15-HpETE, leading to a collapse of mitochondrial membrane potential (ΔΨm) and subsequent IP3R-mediated calcium (Ca²⁺) efflux. This Ca²⁺ surge initiates the assembly of NLRP3 inflammasome, driving GSDMD-dependent pyroptosis. Thus, ALOX15 acts as a keystone regulator bridging oxidative stress to pyroptosis via a mitochondria-Ca²⁺-pyroptosis axis. This axis functions independently of the organ type and is transmitted through both parenchymal and hematopoietic cells, suggesting that thiolox and targeted ALOX15 inhibition could be viable strategies for protecting multiple organs from I/R injury.

Acute ischemic stroke, a leading cause of neurological disability, stemed from cerebral hypoperfusion-induced ischemia/reperfusion (I/R) injury. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death, has emerged as a key pathological driver. Unlike apoptosis, ferroptosis involves glutathione peroxidase 4 (GPX4) inactivation, iron dysregulation, and lethal lipid peroxides. Its preclinical inhibition reduced neuronal loss, demonstrating therapeutic promise. Ischemic injury activated accidental/regulated cell death pathways, with ferroptosis, apoptosis, and pyroptosis dynamically regulated by ischemia duration/severity. Convergent mechanisms included hypoxia-induced mitochondrial dysfunction, iron/lipid peroxidation disrupting blood-brain barrier integrity, glutamate-ferroptosis oxidative crosstalk, and Ca²⁺ overload via reversed Na⁺/Ca²⁺ exchange and NMDA hyperactivity. Clinically, cerebrospinal ferritin elevation and parenchymal iron deposition predicted poor outcomes, prioritizing iron homeostasis modulation. GPX4 activation, ACSL4/LOX inhibition, and ACSL3-mediated MUFA integration have showed efficacy in preclinical models. Translational barriers included poor blood-brain barrier permeability of inhibitors, unvalidated human pathways, and lack of relevant comorbid models. Advancing therapies required biomarker discovery, human tissue validation, and integrated models to bridge mechanisms and clinical translation. Ferroptosis inhibition emerged as a neuroprotective strategy with transformative therapeutic potential for acute ischemic stroke, offering a novel avenue to mitigate neuronal injury and improve clinical outcomes.

Alzheimer’s disease (AD) and late-life depression (LLD) patients both exhibit peripheral motor nerve conduction impairments, but with distinct patterns, highlighting divergent neurophysiological mechanisms in these aging-related disorders. To compare peripheral nerve conduction function among normal cognition (NC), older adults with AD, and LLD. All the participants were enrolled and assigned to AD, LLD and aged-matched NC controls (all ≥60 years, n=60, respectively). Sensory conduction of the median and sural nerves, and motor conduction of the median and common peroneal nerves, were assessed. Key parameters included latency, amplitude, and conduction velocity. Group differences were analyzed after adjusting for gender, age, education, height, and comorbid medical conditions. By controlling gender, age, height, education level, and somatic diseases with inter-group differences, compared with NC group, the median nerve motor conduction in AD group showed prolonged proximal latency (3.21 vs. 3.65 ms, P=0.023), reduced amplitude (proximal: 7.30±2.02 vs. 3.89±0.57 mV; distal: 6.13±2.17 vs. 4.12±2.38 mV, both P<0.001), and slowed conduction velocity (56.46±5.18 vs. 49.29±6.27 m/s, P=0.002). LLD group exhibited more pronounced latency prolongation (proximal: 3.21 vs. 4.06 ms; distal: 7.18 vs. 7.98 ms, both P<0.001) and greater amplitude reduction (proximal: 7.30±2.02 vs. 3.65±0.66 mV; distal: 6.13±2.17 vs. 3.18±1.88 mV, both P<0.001). In terms of the common peroneal nerve motor conduction, function AD group had significantly slower conduction velocity (48.88±5.82 vs. 42.85±5.27 m/s, P=0.033). LLD group showed prolonged proximal latency (4.25 vs. 5.77 ms, P<0.001). No significant differences were found in sensory conduction parameters across groups after adjustment. Both AD and LLD groups were associated with peripheral motor neuropathy, but the pattern of impairment differs. AD is marked by generalized conduction slowing, while LLD shows more severe latency delays and amplitude loss, suggesting distinct pathophysiological pathways. These findings provide new insights into the peripheral nervous system’s involvement in age-related neurocognitive and mood disorders.