Neurons require protective systems throughout their entire life course to function prop-erly. However, the brain remains highly susceptible to injury with modern environmental dynamics, when threats, produced naturally and synthetically, can bypass the blood-brain barrier (BBB) and cause neurological damage. Among those toxicants, atrazine (ATZ) has been regarded as a neurotoxic environmental pollutant. Both low-dose exposure and variable courses (short- and long-term) carried out in different experimental models demonstrated that ATZ impairs multiple neurochemical pathways. The resultant disruption leads to oxidative stress, mitochondrial dysfunction, and neuroinflammation, culminating in neuronal injury and impaired function. Despite the limited number of existing studies, bioactive compounds such as lycopene, isoflavones, and biflavanone kolaviron have been shown to be promising neuroprotective agents against ATZ neurotoxicity. These compounds, derived from natural bioactive tomato, soybean, walnut, and bitter kola- Garcinia kola, respectively, possess antioxidant and neuroprotective potentials, thus capable of mitigating the toxic actions of ATZ exposure. Overall, in vitro and in vivo studies accentuate that plant-derived bioactive compounds offer therapeutic benefits in mitigating neurotoxicity from ATZ. However, further research is needed to elucidate the detailed mechanisms by which the plants bioactive compounds mitigate ATZ-induced neurotoxicity, including their interactions with the pathways involved in the neurotoxic effects of ATZ.

Healthy soils and clean water are essential for human survival, yet, both are increasingly compromised by chemical and plastic pollution. This preventable crisis causes an estimated 9 million premature deaths each year, including about 0.9 million linked to soil pollution and 1.3 million to water pollution. In 2019 alone, pollution contributed to 5.5 million cardiovascular deaths, underscoring its role in the global burden of non-communicable disease. A key underrecognized driver is the rapid rise in plastic production and plastic-associated chemicals. Global plastic output has increased more than 250-fold since 1950 and is projected to nearly triple by 2060, while less than 10% is effectively recycled. As highlighted by the Lancet Countdown on health and plastics, plastics threaten human health across their lifecycle, from fossil fuel extraction to waste, fragmentation, and environmental persistence. Soils and water systems are increasingly contaminated by heavy metals, pesticides, persistent synthetic chemicals, and micro- and nanoplastics. These pollutants degrade soil, reduce agricultural productivity, contaminate food chains, and spread through aquatic ecosystems, thereby amplifying disease risk. Micro- and nanoplastics have been detected in human blood, placenta, brain, and cardiovascular tissues, raising concern about biological effects. These exposures are drivers of cardiovascular disease. Despite their chemical diversity, they converge on shared mechanisms, including oxidative stress, inflammation, endocrine disruption, and circadian dysregulation. Their persistence reflects policy failure. Reducing soil, water, and plastic pollution must become a central pillar of cardiovascular prevention through enforceable, lifecycle-based policies that protect human health. #These authors contributed equally and should be considered as joint first and joint last authors.

Skin is among the most frequent sites of cancer diagnosis, and the global incidence of skin cancer continues to rise despite extensive public health initiatives and preventive strategies. Arsenic, a ubiquitous environmental metalloid classified as a Group 1 carcinogen, remains an important concern due to widespread exposure through contaminated drinking water, food sources and occupational contact. Arsenic‑associated skin carcinogenesis involves complex, interdependent molecular processes and has been linked to the disruption of redox signalling, altered DNA damage signalling and repair responses as well as epigenetic reprogramming. In keratinocytes, arsenic perturbs redox and stress‑response pathways and may disrupt genome maintenance and cellular stress signalling in experimental systems. Arsenic may also alter microRNA networks and affect telomere and mitochondrial homeostasis, although the contribution of these processes to malignant transformation remains context‑dependent; in melanoma, the carcinogenic mechanisms of arsenic are less well characterized. Clinically, arsenic is recognized as a carcinogen in non‑melanoma skin cancer (NMSC) and evidence from high‑exposure endemic regions, together with occupational cohorts, suggest a dose‑responsive association. For melanoma, clinical evidence is more heterogeneous and subject to substantial potential confounding, although some studies suggest modest risk elevation in high‑exposure or occupational settings. Collectively, convergent mechanistic, experimental and epidemiological data support arsenic as an independent carcinogen, particularly in NMSC. These findings underscore the need for heightened clinical vigilance, particularly in exposed populations, and call for renewed public health strategies and regulatory frameworks to mitigate the persistent global burden of arsenic‑associated skin cancer.

Neurological disorders are a major public health concern. Notably, the rate of chronic neurological diseases is affected by lifestyle changes, leading to considerable health-care and economic burden worldwide. Considerable interest has emerged on functional foods due to their beneficial health efficacy. Thus, efforts have been made to extract different bioactive phytochemicals or compounds from therapeutic natural-based products, which has led to functional foods referred to as "vitafoods,""medifoods," "pharmafoods," or "medicinal foods." To overcome neurological illness such as obsessive-compulsive disorder (OCD), nutraceuticals have been applied as prophylactic options This review addresses nutraceutical intervention in the OCD treatment.

Antimony (Sb) is a toxic metalloid and a global pollutant. Sb exposure is known to cause pulmonary, cardiovascular, liver and kidney damage, as well as cancer. In addition, data showing neurotoxic effects of Sb have been also obtained recently. Therefore, the objective of the present review was to discuss existing epidemiological findings linking Sb exposure to brain diseases and the underlying molecular mechanisms of Sb neurotoxicity. Laboratory findings revealed neurotoxic effects of high-dose Sb exposure. Specifically, in vitro and in vivo studies show that Sb induces neuronal apoptosis through induction of oxidative stress, altered Akt/mTOR and Wnt/β-catenin signaling, and potentially increased Ca2 + flux. Activation of ferroptosis due to reactive oxygen species (ROS) overproduction, autophagic GPX4 degradation, and NCOA4-mediated ferritinophagy also appear to mediate Sb neurotoxicity. Other mechanisms linked to adverse effects of Sb in brain include altered neurotransmitter metabolism, neuroinflammation, as well as impaired gut-brain axis and neurogenesis. Epidemiological findings show also that Sb exposure, both in single metal and multiple metal exposure models, is associated with increased risk of depression, sleep disorders, anxiety, cognitive dysfunction, and neurodevelopmental disorders like autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), although controversial data exist. Evidence showing that maternal Sb exposure is also associated with adverse neurodevelopmental outcome in children also exists. While the precise role of Sb exposure in development of neurological diseases has yet to be established due to limited data, a complex of epidemiological and laboratory findings show that Sb should be considered a potential environmental neurotoxicant.

Selenium (Se) and selenoproteins play a significant role in preventing mitochondrial damage. Se regulates mitochondrial dynamics, biogenesis, and mitophagy, but the mechanisms by which it controls mitochondrial quality remain to be fully characterized. Thus, the objective of this review is to address the underlying mechanisms of Se in regulation of mitochondrial quality control upon exposure to endogenous and exogenous stressors. Contemporary data show that Se deficiency is associated with a shift from mitochondrial fusion to fission, inhibition of mitochondrial biogenesis via down-regulation of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/nuclear respiratory factor 1 and 2 (NRF1/2)/mitochondrial transcription factor A (TFAM) signaling, and alterations in PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in vitro and in vivo. The role of Se in regulating mitochondrial quality control is mediated by specific selenoproteins, as evidenced from experimental selenoprotein knockout and overexpression models. Correspondingly, treatment with various forms of Se attenuates inhibitory effect of endogenous stressors (oxidative stress, ischemia, etc.), as well as exogenous agents like heavy metals, ammonia, fluoride, mycotoxins, and paraquat, on mitochondrial fusion/fission balance and biogenesis. Administration of Se mitigates the adverse effects of these stressors on mitophagy by recovering impaired mitophagy or by inhibiting mitophagy overactivation. Therefore, Se treatment might be considered a therapeutic approach to mitigate the adverse effects of various stressors on mitochondrial quality control and functioning, leading to prevention of liver, kidney, brain, and intestinal damage. However, the specific mechanisms, as well as dose-response and species-specific effects have yet to be investigated.

Mercury (Hg) is a ubiquitous heavy metal known for its neurotoxic effects, with its impact on the nervous system critically influenced by its chemical speciation. Its natural sources include volcanic activity, geological deposits, geothermal springs, and oceans. In contrast, human activities- such as industrial processes, gold mining, hazardous waste incineration, and fossil fuel combustion- further contribute to environmental Hg levels. Exposure to Hg, primarily through inhalation, ingestion, or skin contact, can result in significant neurological damage. Hg exists in various forms, with methylmercury (MeHg) being the most toxic, readily accumulating in brain tissue. In vitro and in vivo studies indicate that MeHg disrupts synaptic transmission, impairs neuronal signaling, alters cell structure, induces oxidative stress, triggers inflammatory responses, and causes both necrotic and apoptotic cell death. These disturbances can manifest as cognitive deficits, mood disorders, and motor dysfunction. Moreover, Hg's ability to cross the blood-brain barrier exacerbates its neurotoxic potential, leading to long-lasting effects even after exposure ceases. Given its socio-economic impacts, Hg contamination and the resulting exposure of humans and wildlife have prompted policies and regulations aimed at reducing emissions from human activities. In this context, this review summarizes the major sources and health impacts of Hg exposure, with a particular focus on the mechanisms of MeHg-induced neurotoxicity. We highlight evidence from experimental models that implicates oxidative stress, neuroinflammation, and cell death as central pathways underlying its harmful effects on the nervous system.

Selenoneine, an antioxidant molecule analogous to ergothioneine, is not synthesized by vertebrates but can be acquired through the diet. Both selenoneine and ergothioneine contain redox-active groups: selone (-C=Se) and thioketone (-C = S), respectively. However, the reactivity of the selone group with pro-oxidant intermediates is significantly higher than that of the thioketone group. In the presence of oxygen, selenoneine undergoes oxidation to its diselenide form, which can be regenerated by a molar excess of reduced thiol groups. High levels of selenoneine have been detected in carnivorous fish, aquatic mammals, and populations consuming these species. It has been suggested that both selenoneine and ergothioneine possess health-promoting properties in humans. This chapter explores the potential protective effects of selenoneine against electrophilic mercury forms, such as methylmercury (CH3Hg+) and divalent mercury (Hg2 +).

Combined manganese (Mn) and iron (Fe) exposure is increasingly recognized as a risk factor for neurotoxicity, but the underlying mechanisms and potential interventions remain incompletely understood. Here, PC12 cells and Sprague-Dawley rats were used to investigate neuroinjury induced by combined Mn-Fe exposure and the potential protective effects of sodium para-aminosalicylate (PAS-Na). Cognitive performance was evaluated using the Morris water maze and Y-maze, whereas histopathological changes, regional Mn and Fe accumulation, oxidative-inflammatory injury, Wnt/β-catenin/GSK-3β-related proteins, Tau/Aβ-related alterations, and apoptosis were assessed in PC12 cells and in the hippocampus and cortex of rats. Combined Mn-Fe exposure induced marked neuroinjury, characterized by impaired spatial learning and memory, neuronal damage in the hippocampus and cortex, increased regional brain Mn and Fe burden, enhanced oxidative stress and neuroinflammation, Tau/Aβ-related abnormalities, apoptosis, and alterations in Wnt/β-catenin/GSK-3β-related protein expression. PAS-Na attenuated these alterations, with medium and high doses generally showing more consistent effects than the low dose. PAS-Na treatment was associated with reduced Mn and Fe accumulation in cognition-related brain regions, partial normalization of Wnt/β-catenin/GSK-3β-related protein expression, and attenuation of oxidative-inflammatory injury and neuropathological changes. These novel findings indicate that PAS-Na partially alleviates combined Mn-Fe-induced neuroinjury and is associated with reduced regional metal burden, oxidative-inflammatory injury, apoptosis, and changes in Wnt/β-catenin/GSK-3β-related signaling.

Neurodegeneration is characterized by disruptions in metabolic signaling that drive neurons into dysfunctional states, compromising cellular integrity and ultimately leading to cell death. Tryptophan (TRP) metabolism through the kynurenine pathway (KP) plays a central role in neurotransmission, redox balance, and energy metabolism. Alterations in this pathway have been implicated in numerous neurodegenerative conditions. Redox homeostasis is largely governed by the Keap1/Nrf2/ARE pathway, which coordinates the transcription of antioxidant and detoxification responses; however, disruption of this axis exacerbates oxidative stress and neuroinflammation. In turn, the IκBα/NF-κB/IRE pathway controls immune-driven inflammatory states. Crosstalk between these pathways maintains the integrity of metabolic signaling, supporting the adequate functioning of the CNS. In this review, we examine evidence demonstrating that these pathways engage in tight bidirectional communication, with each influencing the other, thereby offering new avenues for investigation in this field. In addition, we conducted bioinformatic analyses to identify potential antioxidant response elements (AREs) and inflammatory response elements (IREs) within the promoter regions of several KP genes, where multiple heterodimers may bind and modulate transcription. Together, the evidence reviewed and our bioinformatic findings support the concept that these pathways engage in reciprocal crosstalk, forming a coordinated signaling axis that preserves CNS homeostasis and helps prevent neurodegeneration.

Human biomonitoring of mercury (Hg) exposure commonly relies on blood and hair measurements, often assuming a stable conversion ratio between these matrices. However, this assumption neglects dynamic toxicokinetic processes governing Hg distribution and elimination. Here, we characterized the distribution, determinants, and toxicokinetic implications of the hair-to-blood total Hg ratio in 453 individuals from Amazonian riverine communities chronically exposed to methylmercury (MeHg). Total Hg (THg) was determined in blood and hair, Hg speciation in hair by LC-ICP-MS, and selenium (Se) in blood was measured by ICP-MS. Model-based estimates of MeHg intake and Hg excretion were derived, and linear, non-linear, and multivariable analyses were applied. Blood and hair THg were strongly correlated (R = 0.86, p < 0.0001), confirming hair as a robust biomarker of chronic exposure. However, the hair-to-blood ratio showed high inter-individual variability (median 303; range 73.6-2132) and a significant inverse association with blood THg (β = -0.394, p < 0.001), indicating non-linear partitioning. Blood Se levels were elevated and positively associated with the ratio (β = 1.081, p < 0.001). Estimated MeHg intake exceeded the USEPA reference dose by over tenfold. These findings demonstrate that the hair-to-blood Hg ratio is a dynamic biomarker influenced by exposure intensity and potentially by Se status.

For more than four decades, research on Amazonian riverine populations has been shaped by a single dominant narrative: that mercury (Hg) exposure from fish consumption is the primary driver of neurotoxic risk. While this perspective was pivotal in raising global awareness of methylmercury (MeHg) hazards, it has also constrained scientific inquiry, often obscuring the multifactorial vulnerabilities that characterize these communities. This commentary challenges that reductionist framework by integrating evidence demonstrating a far more complex exposure mosaic. In addition to Hg, riverine populations experience substantial co-exposure to lead (Pb) and potentially to cyanogenic compounds released from cassava processing, a plausible but still insufficiently validated pathway. These exposures intersect with chronic malnutrition, micronutrient deficiencies, and infectious disease, converging on shared toxicodynamic pathways such as oxidative stress, calcium dysregulation, mitochondrial injury, and endocrine disruption. Epidemiological data reveal that blood Hg and Pb concentrations strongly covary and increase concurrently with fish and cassava flour intake, reflecting intertwined dietary patterns rather than independent exposure routes. This collinearity raises the possibility that reported associations between Hg biomarkers and neurological outcomes may represent toxicological misattribution, where co-exposures and nutritional deficits, not MeHg alone, account for observed effects. Persisting in a mercury-centric paradigm has simplified Amazonian environmental health and guided policy, funding, and scientific attention toward a single contaminant, often at the expense of urgent health determinants such as anemia, food insecurity, impaired sanitation, and persistent infections. Reframing Amazonian toxicology through an exposome-driven, systems-oriented perspective, integrating multi-exposure biomonitoring, nutritional profiling, and longitudinal omics, offers a more accurate foundation for causal inference and more equitable public health action. This holistic approach is essential to understanding how intertwined environmental, nutritional, and social exposures shape neurodevelopmental and neurological health in Amazonian riverine populations.

Methylmercury (MeHg) and manganese (Mn) are environmental contaminants widely distributed in the Earth's crust and are associated with neurotoxicity, particularly affecting dopaminergic function. While both metals are known to share common toxicity pathways, such as mitochondrial dysfunction and dopaminergic neurodegeneration, limited research has explored the combined effects of MeHg and Mn exposure. Using Caenorhabditis elegans ( C. elegans ) as a model, we assessed the effects of acute co-exposure to MeHg and Mn on survival, dopaminergic neuron integrity, behavior analysis and mitochondrial function via high-resolution respirometry. Our results show that co-exposure reduced worm survival and body size and caused dopaminergic neuron disruptions, impaired locomotion, reduced basal slowing response (BSR), and increased swimming-induced paralysis (SWIP). Mitochondrial dysfunction was also evident, with Mn-induced impairment of mitochondrial respiration, while co-exposure led to possible compensatory increases in several mitochondrial activities, including OXPHOS CI and citrate synthase activity. The differential sensitivity of these endpoints to the metal combination underscores the importance of evaluating co-exposure scenarios to capture a more comprehensive view of the potential neurotoxic risks associated with environmental contaminants upon real-life exposure scenarios. These findings highlight the need to assess combined exposures, particularly in environments with complex contamination profiles, as the neurotoxic risks may exceed those observed with individual toxicants.

Lead (Pb) is a widely distributed environmental pollutant that is highly noxious due to its toxicokinetic characteristics. Pb exposure can damage vital organ systems, including the central nervous and stomatognathic systems. As salivary glands play an important role in oral homeostasis, this study aimed to investigate the effects of maternal Pb exposure during pregnancy and lactation on the salivary glands of rat male offspring. Six 90-day-old pregnant Wistar rats were randomly divided into two groups of three animals each: a control group and a lead acetate group (treated with 50 mg/kg lead acetate for 21 days during pregnancy and 21 days during lactation). After the exposure period, the submandibular and parotid glands of the male offspring were collected for biochemical, morphometric, and histochemical analyses, and the findings were analyzed using the Student's t-test or Mann-Whitney U test. Maternal Pb exposure significantly decreased the antioxidant capacity (52%, p < 0.001) and increased lipid peroxidation (105%, p < 0.001) and nitrite levels (106%, p < 0.01) in both parotid and submandibular glands. Morphological analysis of the parotid gland showed an increase in the total stromal area and a decrease in the acinar area compared to the control group, whereas in the submandibular gland, there was an increase in the stromal, acinar, and duct areas in the Pb-exposed group. The histochemical analysis revealed no difference in the average collagen area between the groups. The alterations found may compromise glandular development and salivary function, indicating that early-life Pb exposure poses long-term risks to oral homeostasis.

Underutilized legumes represent an untapped frontier in food, nutrition, and health security. Among them, rice bean (Vigna umbellata) stands out for its nutritional richness, ecological resilience, and therapeutic potential, yet remains marginalized in global food systems. Despite its adaptability to heat, drought, and marginal soils, it suffers from limited phytochemical profiling. Similarly, sparse genomic and omics resources, and weak translational evidence linking bioactives to human health. This review compiles advances in phytochemical mapping, highlighting regional variations in flavonoids, phenolic acids, bioactive peptides, and low-glycemic starch. Comparative positioning against major legumes underscores its potential compositional advantages associated with antioxidant and metabolic relevance. Emerging genomic, transcriptomic, metabolomic, and proteomic studies reveal untapped breeding potential, while systems biology and AI-driven omics integration promise accelerated trait improvement. We argue for positioning rice bean as a climate-smart crop within circular and sustainable farming systems, with roles in nitrogen fixation, metabolic health, and functional food innovation. Bridging policy frameworks, market incentives, and interdisciplinary collaborations is critical to elevate rice bean from orphan status to a strategic crop for nutrition-sensitive agriculture. This narrative review synthesizes current compositional, multi-omics, and systems-level evidence on rice bean (Vigna umbellata), without employing a systematic literature search or meta-analytical framework. It is concluded with a translational roadmap, outlining integrative research priorities across plant sciences, pharmacology, and socioeconomics to unlock rice bean's potential as a cornerstone of future-ready food systems.

The objective of the present review is to discuss the protective effects of SeNPs against metal toxicity with special emphasis on the underlying mechanisms and efficacy of SeNPs in comparison to other Se species. In vivo and in vitro studies show that SeNPs mitigate the adverse effects of metal(loid)s (cadmium, lead, arsenic, aluminum, etc.), metal nanoparticles (silver, cobalt), as well as platinum-based agent cisplatin in brain, liver, kidneys, heart, intestine, and gonads. SeNPs substantially reduce toxic metal accumulation in the organism, thus attenuating their toxicity. In metal-exposed animals, SeNPs enhance the biosynthesis of selenoproteins (including GPX4) and up-regulate Nrf2 signaling, thus inhibiting oxidative stress and ferroptosis. Anti-inflammatory effect of SeNPs was shown to be mediated by inhibition of NF-κB and MAPKs, as well as activation of PI3K/Akt signaling. Inhibition of metal-induced endoplasmic reticulum stress and improvement of autophagy also underlies the protective effects of SeNPs. Neuroprotective effects of SeNPs were shown to be mediated by inhibition of metal-induced increase in amyloid β and Tau protein accumulation and aggregation. The majority of studies show that SeNPs possess stronger protective effect against metal toxicity compared to sodium selenite or organoselenium compounds. Furthermore, the beneficial effects of SeNPs in metal-exposed animals were significantly increased by combined administration or surface modifications with bioactive molecules. Taken together, these findings show that SeNPs possess protective effects against metal toxicity through a variety of mechanisms, although their potential efficacy in treatment metal intoxication in humans has yet to be determined.

Neuropsychiatric disorders are of great health concerns, and despite the availability of drugs, effective therapies are poor, emphasizing the need for novel therapeutics. Among the natural substances screened for neuromodulation properties, Spirulina platensis, a cyanobacterium, and its main bioactive compound (phycocyanin) have attracted great attention. Substantial evidence demonstrates that spirulina and phycocyanin possess neuroprotective properties by targeting multiple interconnected cellular and molecular pathways, including apoptosis, oxidative stress, neuroinflammation, and regulators of synaptic plasticity. Consequently, these compounds have shown therapeutic potential in experimental models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, cerebral ischemia, epilepsy, schizophrenia, depression, and autism spectrum disorder. Herein, we summarize various cellular and molecular pathways which are affected by spirulina and phycocyanin in neuropsychiatric disorders.

Phthalates are ubiquitous environmental contaminants and endocrine-disrupting chemicals used as plasticizers in consumer products, medical devices, and industrial materials. Evidence from in vitro experiments, animal models, and epidemiological studies suggests that phthalate exposure particularly to di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP), may induce neurotoxicity through multiple interconnected mechanisms. The developing brain is especially vulnerable, with prenatal and early-life exposures linked to cognitive deficits, behavioral abnormalities, and neurodevelopmental disorders. Conventional therapeutic options remain limited, highlighting the need for effective neuroprotective strategies. Natural bioactive compounds such as polyphenols, flavonoids, carotenoids, and other phytochemicals have been investigated as potential neuroprotective candidates in preclinical models owing to their multi-target mechanisms (e.g., antioxidant, anti-inflammatory, and neurotrophic actions), potent antioxidant capacity, and regulation of cellular signaling pathways. Preclinical studies demonstrate that lycopene, ferulic acid, coenzyme Q10, omega-3 fatty acids, vanillic acid, and Moringa oleifera extracts attenuate phthalate-induced neurotoxicity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, suppressing nuclear factor-kappa B (NF-κB)-mediated inflammation, modulating MAPK/ERK and PI3K/Akt signaling, and restoring brain-derived neurotrophic factor (BDNF)/TrkB support. Despite these promising findings, challenges persist, including poor bioavailability, lack of standardized dosing, and limited human clinical trials. A structured review of experimental and epidemiological studies was conducted using predefined inclusion criteria. This review integrates evidence across in vitro, in vivo, and human studies to identify key mechanisms of phthalate-induced neurotoxicity, including oxidative stress, neuroinflammation, endocrine disruption, epigenetic dysregulation, and impaired neuroplasticity, and evaluates pathway-specific neuroprotective actions of bioactive compounds while highlighting critical translational gaps.

The LKB1-AMPK signaling pathway is a central regulator of hepatic energy homeostasis and is increasingly implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). LKB1-mediated AMPK activation promotes fatty acid β-oxidation, autophagy, and mitochondrial biogenesis. At the same time, it suppresses de novo lipogenesis, cholesterol synthesis, and mTOR-dependent anabolic growth, thereby supporting hepatic lipid and energy balance. Impairment of this pathway may disrupt hepatic lipid homeostasis and promote triglyceride accumulation. Oxidative stress, microRNA dysregulation, hormonal imbalance, copper dysregulation, and inflammatory mediators can further contribute to mitochondrial injury, hepatocellular apoptosis, and inflammatory activation. These processes may facilitate progression from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocarcinogenesis. LKB1-AMPK signaling also intersects with immunometabolic and stromal pathways. Defects in hepatic immune and stromal compartments may enhance pro-inflammatory Th17 responses and fibrogenic transformation. Therapeutically, pharmacologic activation of LKB1-AMPK has shown context-dependent cytoprotective potential, mainly in preclinical models. Natural compounds, synthetic small molecules, repurposed agents, and nutrient-derived modulators can activate LKB1-AMPK signaling. These interventions reduce steatosis, oxidative stress, and endoplasmic reticulum stress while enhancing autophagic flux and fatty acid catabolism. Additional benefits may arise through gut microbiota-mediated signaling that converges on LKB1-AMPK-dependent metabolic restoration. Overall, the LKB1-AMPK axis links nutrient sensing, mitochondrial function, redox control, and inflammatory regulation in NAFLD pathophysiology. Current evidence supports further development of pathway-targeted interventions, but clinical translation requires stronger human validation.