Cigarette smoke (CS) is a major risk factor for both acute and chronic diseases, predominantly impacting the lungs and cardiovascular system. Increasing evidence indicates that CS also has substantial but underappreciated effects on liver health, including accelerating the progression of alcoholic liver disease (ALD). Because smoking and alcohol consumption often co-occur in clinical populations, understanding their combined effects is important for translational research. This study aimed to elucidate the mechanisms by which CS intensifies ALD through a comprehensive assessment of histopathological changes, biochemical indices, and molecular alterations in the liver. Six-week-old male C57BL/6 mice were initially exposed to three concentrations of CS (150, 300, and 600 μg/L) or filtered air for 2 h per day, 5 days each week, and then administered ethanol to induce ALD. Exposure to CS markedly worsened alcohol-induced liver injury, as evidenced by higher serum alanine aminotransferase and aspartate transaminase activities, increased hepatic lipid accumulation, enhanced oxidative stress, and elevated inflammation. Mice subjected to both CS and ethanol displayed more pronounced hepatic injury than those exposed to either stimulus alone, suggesting an additive deleterious effect that accelerates ALD progression. Importantly, CS strongly induced hepatic cytochrome P450 enzymes, particularly CYP1A2 and CYP2E1, thereby enhancing ethanol metabolism and worsening ALD progression. This mechanistic effect provides an insight that contributes a notable element of novelty to the study. Confirmatory results were observed in ex vivo studies, where primary hepatocytes treated with various concentrations of CS extract and 100 mM ethanol showed comparable injury patterns and CYP induction. Overall, these results indicate that CS exposure exacerbates ALD development, partially through the modulation of hepatic cytochrome P450 enzyme activity.

BACKGROUND:The pathogenesis of liver fibrosis centres on the activation of hepatic stellate cells (HSCs). Adenosine-to-inosine RNA editing, primarily catalysed by adenosine deaminase acting on RNA1 (ADAR1), is the most prevalent post-transcriptional modification that increases transcriptome diversity. OBJECTIVE:This study aims to elucidate the role of ADAR1-imposed RNA editome in HSC activation and to determine the therapeutic potential of targeting ADAR1 for liver fibrosis. DESIGN:ADAR1 expression was measured in fibrotic human and mouse livers, as well as in primary human and mouse HSCs. Adar1 loss-of-function effect was evaluated in Adar1f/f /Cre-ER, Adar1△HSC and Adar1i△HSC mice, whereas viral infection with Ad-Adar1 was employed in gain-of-function studies. Adar1△HSCIfih1-/-- and Adar1△HSCIfnar△HSC mice were used for mechanistic studies. An ADAR1 inhibitor and HSC-selective RNAi were used for therapeutic evaluations. RESULTS:ADAR1 is decreased in human and mouse fibrotic livers and activated HSCs. HSC-specific ablation or pharmacological inhibition of ADAR1 ameliorated HSC activation and liver fibrosis. In contrast, forced expression of ADAR1, but not its editing-deficient mutant, exacerbated HSC activation. Mechanistically, ADAR1 ablation accumulated double-stranded RNA and activated HSC-intrinsic innate immunity in a melanoma differentiation-associated gene 5-dependent manner. Interferon-β was identified as a key antifibrotic effector via the activation of the JAK1/2 pathway. RNA editome analysis revealed the Col3a1 3' UTR as a novel ADAR1 editing target, leading to increased collagen production. CONCLUSION:ADAR1-imposed RNA editome suppresses HSC-intrinsic innate immunity and promotes collagen production, leading to aggravated HSC activation and liver fibrosis. Targeting ADAR1 with its pharmacological inhibitor or HSC-selective RNAi shows great promise in treating liver fibrosis.

Wang et al. recently proposed mitoxyperiosis as a previously uncharacterized, mitochondria-dependent form of lytic cell death triggered by immunometabolic stress. Unlike apoptosis, pyroptosis, necroptosis, or ferroptosis, mitoxyperiosis is driven by sustained oxidative stress and prolonged mitochondria-plasma membrane contact, culminating in localized oxidative membrane damage and non-caspase-dependent rupture, termed mitoxyperilysis. Central to this mechanism is the activation of mechanistic target of rapamycin complex 2 (mTORC2), which suppresses actin cytoskeletal remodeling and inhibits lamellipodia formation, thereby retaining mitochondria at the cell periphery. Remarkably, mTORC2 inhibition or the restoration of cytoskeletal dynamics prevents membrane rupture despite persistent oxidative stress. This review synthesizes mechanistic insights and experimental evidence underlying mitoxyperiosis and examines its implications for tumor biology and inflammatory disease. We further discuss how this pathway may expand current understanding of spatial control in regulated cell death and may provide therapeutic opportunities targeting mitochondrial positioning and mTORC2 signaling in immunometabolic disorders.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury and is associated with high mortality. G protein-coupled receptor kinase 2 (GRK2) is a widely expressed serine/threonine kinase involved in the regulation of multiple cellular signaling pathways. Dysregulation of GRK2 expression has been linked to numerous pathological states, highlighting its potential contribution to disease mechanisms. However, its involvement in drug-induced acute liver injury is yet to be elucidated. This study explored the hepatoprotective effects of paroxetine, a GRK2 inhibitor, in the context of APAP-induced liver injury. Male C57BL/6 mice received an intraperitoneal injection of APAP (300 mg/kg), followed by oral administration of paroxetine (10 mg/kg) 30 min afterward. Paroxetine markedly decreased serum alanine aminotransferase and aspartate aminotransferase concentrations and reduced APAPinduced hepatocellular apoptosis and inflammation. Paroxetine also diminished hepatic neutrophil accumulation and decreased the expression of pro-inflammatory cytokines and chemokines. Furthermore, GRK2 inhibition alleviated oxidative stress, as evidenced by lower hepatic malondialdehyde concentrations and a partially restored glutathione (GSH)/GSH disulfide ratio. Importantly, inhibition of GRK2 resulted in a decrease in hepatic phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results indicate that pharmacological inhibition of GRK2 by paroxetine confers protection against APAP-induced hepatotoxicity through antiinflammatory and antioxidant actions, potentially mediated by modulation of ERK signaling.

Signal transducer and activator of transcription 1 (STAT1) is a central regulator of interferon signaling, antiviral defense, inflammation, and antitumor immunity. Although STAT1 activation has been traditionally defined by phosphorylation, recent studies have revealed diverse post-translational modifications (PTMs) that fine-tune its activity, stability, localization, and transcriptional output. Newly identified modifications, including vitamin C-derived vitcylation and pyruvate-induced pyruvylation, directly link nutrient and metabolic cues to STAT1 signaling. Additional PTMs, such as acylation, glycosylation, ubiquitination, methylation, and oxidative modifications, further shape STAT1 function in a context-dependent manner. In this review, we evaluate the evidence supporting STAT1 PTMs and discuss how specific modifications regulate STAT1 activation, stability, localization, and transcriptional output in immune and inflammatory contexts, while distinguishing established regulatory mechanisms from emerging modifications that require further validation.

Acetaminophen [N-acetyl-p-aminophenol (APAP)] overdose is a leading cause of acute liver failure worldwide, chiefly due to its hepatotoxic effects. The pathogenesis of APAP-induced acute liver injury (ALI) involves complex interactions among various hepatic cell types, each playing a distinct role in the progression of the injury. Hepatocytes, the primary targets of APAP toxicity, undergo oxidative stress, mitochondrial dysfunction, and necrosis following the formation of the toxic metabolite N-acetyl-p-benzoquinone imine. Additionally, other hepatic cells and infiltrating immune cells responding to liver injury significantly contribute to the pathogenesis of APAP-induced ALI. This review synthesizes current mechanistic insights to offer a detailed understanding of the specific contributions of hepatic cells to APAP-induced liver injury, emphasizing potential therapeutic targets designed to reduce liver damage and enhance patient outcomes. Additionally, it identifies potential therapeutic targets within these cellular pathways that could be leveraged to alleviate liver damage and enhance clinical outcomes for patients affected by APAP overdose.

IMPORTANCE:Chronic liver disease (CLD) is a significant global health concern, often progressing to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma in both humans and animals. Despite substantial research efforts, effective CLD treatments remain scarce. Casein kinase 1 epsilon (CK1ε), a serine/threonine kinase, plays a pivotal role in several critical signaling pathways, including the Wingless/Integrated (Wnt)/β-catenin, HIPPO, and mitogen-activated protein kinase (MAPK) pathways, all of which contribute to liver disease progression. OBSERVATIONS:CK1ε regulates key pathways that drive liver fibrosis, inflammation, and cancer. Its involvement in lipid metabolism and adipogenesis links CK1ε to metabolic dysfunctional-associated steatotic liver disease. Elevated CK1ε levels are observed in disease models beyond CLD, underscoring its broad role in pathological conditions. Moreover, CK1ε phosphorylates critical proteins such as Wnt/β-catenin, RAS/MAPK, phosphoinositide 3-kinase/protein kinase B, transcription coactivators yes-associated protein 1 and the PDZ-binding motif, and Sprouty homolog 2, suggesting potential influence on liver cell function and fibrosis development. Preclinical models demonstrate that CK1ε inhibitors, including PF-4800567, PF-670462, and IC261, effectively reduce tumor growth and fibrosis of variable etiologies. CONCLUSIONS AND RELEVANCE:CK1ε's central role in liver disease progression makes it a compelling target for therapeutic strategies. Targeting CK1ε with small molecules or gene therapies could offer novel treatment avenues for CLD. However, challenges related to target specificity and safety must be addressed. Further research and translational studies could pave the way for precision medicine approaches, enhancing treatment outcomes for both animals and humans with CLD.

Cysteine (Cys) posttranslational modifications play a critical role in regulating protein function, cellular signaling and redox homeostasis in various physiological and pathological conditions. Sulfiredoxin-1 (SRXN1) has emerged as a key regulator of protein redox homeostasis through its involvement in Cys sulfinylation. However, the role of SRXN1 in the pathogenesis of diseases and its therapeutic implications have yet to be fully explored. Beyond its classical function in reactive oxygen species detoxification, SRXN1 also modulates redox-sensitive signaling pathways that govern inflammation, apoptosis and cell survival, making it an essential component of cellular defense against oxidative stress-related damage. Here we highlight the significance of SRXN1 in regulating Cys sulfinylation across a broad spectrum of liver diseases. Furthermore, we emphasize the critical role of SRXN1 in regulating oxidative stress and cellular signaling through its interaction and desulfinylation of target or substrate proteins, both of which are crucial to maintaining cellular function under pathological conditions. Finally, we discuss the potential therapeutic implications of targeting SRXN1 in disease contexts where oxidative stress exacerbates pathological processes. A deeper understanding of SRXN1-mediated redox regulation may offer a novel therapeutic avenue to mitigate Cys oxidation and improve clinical outcomes in various liver disease contexts. Oxidative stress, an imbalance between harmful molecules called reactive oxygen species and the body’s defenses, contributes to many diseases. A key player in managing this stress is a protein called sulfiredoxin 1 (SRXN1). SRXN1 helps to repair proteins damaged by reactive oxygen species, particularly by reversing a process called cysteine sulfinylation, which can impair protein function. This Review explores SRXN1’s role in liver diseases, highlighting its protective effects on hepatocytes under pathological conditions such as acute liver injury, alcoholic liver disease and liver fibrosis. It does this by maintaining redox balance. Researchers used various methods to study SRXN1’s effects, including examining its interactions with other proteins and its impact on cell survival. Results show that, while SRXN1 protects against liver damage, it also aids cancer cell survival in liver cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

BACKGROUND:Cholesterol homeostasis in the human body is a crucial process that involves a delicate balance between dietary cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver. Both pathways contribute significantly to the overall pool of cholesterol in the body, influencing plasma cholesterol levels and impacting cardiovascular health. Elevated absorption of cholesterol in the intestines has a suppressive impact on the synthesis of cholesterol in the liver, serving to preserve cholesterol balance. Nonetheless, the precise mechanisms driving this phenomenon remain largely unclear. SUMMARY:This review aimed to discuss the previously unrecognized role of cholesin and GPR146 in the regulation of cholesterol biosynthesis, providing a novel conceptual framework for understanding cholesterol homeostasis. KEY MESSAGES:The discovery of cholesin, a novel protein implicated in the regulation of cholesterol homeostasis, represents a significant advancement in our understanding of cholesterol biosynthesis and its associated pathways. The cholesin-GPR146 axis could have profound implications across various therapeutic areas concerning abnormal cholesterol metabolism, offering new hope for patients and improving overall healthcare outcomes.

The current letter to the editor pertains to the manuscript entitled 'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'. Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress, oxidative stress, and dysregulated lipid metabolism, impeding hepatocyte apoptosis and necroptosis.

Hepatic stellate cells (HSCs) play central roles in liver disease pathogenesis, spanning steatosis to cirrhosis and hepatocellular carcinoma. These cells, located in the liver's sinusoidal space of Disse, transition from a quiescent, vitamin A -rich state to an activated, myofibroblast-like phenotype in response to liver injury. This activation results from a complex interplay of cytokines, growth factors, and oxidative stress, leading to excessive collagen deposition and liver fibrosis, a hallmark of chronic liver diseases. Recently, HSCs have gained recognition for their dynamic, multifaceted roles in liver health and disease. Attention has shifted toward their involvement in various liver conditions, including acute liver injury, alcoholic and non-alcoholic fatty liver disease, and liver regeneration. This review aims to explore diverse functions of HSCs in these acute or chronic liver pathologies, with a focus on their roles beyond fibrogenesis. HSCs exhibit a wide range of actions, including lipid storage, immunomodulation, and interactions with other hepatic and extrahepatic cells, making them pivotal in the hepatic microenvironment. Understanding HSC involvement in the progression of liver diseases can offer novel insights into pathogenic mechanisms and guide targeted therapeutic strategies for various liver conditions.

Casein kinase 1 epsilon (CK1ε), a member of the serine/threonine protein kinase family, phosphorylates a broad range of substrates. However, its role in the development of chronic liver diseases remains elusive. This study aimed to investigate the role of CK1ε in the development and progression of metabolic dysfunction-associated steatohepatitis (MASH). Hepatocyte-specific CK1ε knockout (CK1εΔHEP) mice were generated by crossbreeding mice with floxed CK1ε alleles (CK1εfl/fl) and Cre-expressing albumin mice. Mice were fed either a Western diet (WD) or a methionine- and choline-deficient diet to induce MASH. CK1εΔHEP was associated with a decreased severity of WD- or methionine- and choline-deficient diet-induced MASH, as confirmed by reduced incidence of hepatic lesions and significantly lower levels of alanine aminotransferase, aspartate aminotransferase, and proinflammatory cytokine tumor necrosis factor (TNF)-α. CK1εΔHEP WD-fed mice exhibited significant amelioration of total cholesterol, triglycerides, and de novo lipogenic genes, indicating that CK1ε could influence lipid metabolism. CK1εΔHEP WD-fed mice showed significantly down-regulated TNF receptor-associated factor (TRAF) 3, phosphorylated (p) transforming growth factor-β-activated kinase 1, p-TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), and p-AKT levels, thereby affecting downstream mitogen-activated protein kinase signaling, indicating a potential mechanism for the observed rescue. Finally, pharmacologic inhibition of CK1ε with PF670462 improved palmitic acid-induced steatohepatitis in vitro and attenuated WD-induced metabolic profile in vivo. In conclusion, CK1ε up-regulates TNF receptor-associated factor 3, which, in turn, causes transforming growth factor-β-activated kinase 1-dependent signaling, amplifies downstream mitogen-activated protein kinase signaling, modifies p-c-Jun levels, and exacerbates inflammation, all of which are factors in WD-induced metabolic dysfunction-associated steatotic liver disease.

Following an injury, the liver embarks on a process that drives the accumulation and reformation of the extracellular matrix, leading to hepatic fibrosis. Type I interferons (IFNs), including IFN-alpha and IFN-beta, play a crucial role in averting chronic liver injury through the activation of IFN-stimulated genes (ISGs), which are instrumental in sculpting adaptive immunity. The role of 2'-5'-oligoadenylate synthase-like protein 1 (OASL1), an antiviral ISG, in the context of liver fibrosis remains to be elucidated. To elicit liver fibrosis, a diet containing 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CC(l)4) were employed to induce cholestatic- and hepatotoxin-mediated liver fibrosis, respectively. Histological analyses of both models revealed that OASL1(-/-) mice exhibited reduced liver damage and, consequently, expressed lower levels of fibrotic mediators, notably alpha-smooth muscle actin. OASL1(-/-) mice demonstrated significantly elevated IFN-alpha and IFN-beta mRNA levels, regulated by the IFN regulatory factor 7 (IRF7). Additionally, OASL1-/- ameliorated chronic liver fibrosis through the modulation of nuclear factor-kappa B (NF-kappa B) signaling. The effect of OASL1 on type I IFN production in acute liver damage was further explored and OASL1(-/-) mice consistently showed lower alanine transaminase levels and pro-inflammatory cytokines, but IFN-alpha and IFN-beta mRNA levels were upregulated, leading to amelioration of acute liver injury. Additionally, the study discovered that F4/80-positive cells were observed more frequently in OASL1(-/-) CCl4 acutely treated mice. This implies that there is a significant synergy in the function of macrophages and OASL1 deficiency. These results demonstrate that in instances of liver injury, OASL1 inhibits the production of type I IFN by modulating the NF-kappa B signaling pathway, thereby worsening disease.

This review investigates the correlation between prenatal tobacco exposure and the risk of liver diseases in offspring. By synthesizing data from clinical trials and animal studies, it provides a comprehensive overview of the potential mechanisms underlying this association. This review begins by analyzing the prevalence of maternal smoking and its impact on fetal development. It then discusses specific liver diseases observed in offspring exposed prenatally to tobacco, such as acute liver injuries and metabolic dysfunction-associated fatty liver disease, and discusses the underlying pathophysiological pathways. Current evidence indicates that altered fetal liver development, oxidative stress, and genetic modifications may predispose offspring to liver diseases. Furthermore, this review highlights the gaps in current research and the need for longitudinal studies to better understand the long-term effects of prenatal tobacco exposure on the liver. The review concludes with recommendations for public health policies aimed at enhancing our understanding of maternal smoking and mitigating its adverse effects on offspring, emphasizing the importance of smoking cessation during pregnancy.

Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring.Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI.Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11.Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.

Concanavalin A (ConA) is a plant lectin that can induce immune-mediated liver damage. ConA induced liver damage animal model is a widely accepted model that can mimic clinical acute hepatitis and immune-mediated liver injury in humans. Toll-like receptor-7 (TLR7), a member of the TLR family, plays a key role in pathogen recognition and innate immune activation. The aim of this study was to examine the role of TLR7 in the pathogenesis of ConA-induced liver injury. Acute liver injury was induced by intravenous injection with ConA in WT (wild-type) and TLR7 knockout (KO) mice. Results showed that attenuated liver injury in TLR7-deficient mice, as indicated by increased survival rate, decreased aminotransferase levels, and reduced pathological lesions, was associated with decreased release of pro-inflammatory cytokines in livers. Consistently, significantly decreased proliferation of CD4+ T cell was detected in ConA-stimulated TLR7-deficient splenocytes, but not in CD3/CD28 stimulated TLR7-deficient CD4+ T cells. Moreover, TLR7 deficiency in KCs specifically suppressed the expression of TNF-α (tumor necrosis factor-α). Depletion of KCs abolished the detrimental role of TLR7 in ConA-induced liver injury. Taken together, these results demonstrate that TLR7 can regulate the expression of TNF-α in KCs, which is necessary for the full progression of ConA-induced liver injury.

Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 μg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice.