Background and aims: Hepatic fibrosis lacks broadly effective therapy, partly because hepatocyte–derived signals governing hepatic stellate cell (HSC) activation remain incompletely defined. METTL3, the catalytic core subunit of the N6–methyladenosine (m6A) methyltransferase complex, has been proven to participate in the progression of liver fibrosis, yet its non–canonical functions in injured hepatocytes remain undefined. We investigated how hepatocyte METTL3 promotes paracrine HSC activation.Methods: Human fibrotic liver tissues and two mouse hepatic fibrosis models were analyzed in this study, including carbon tetrachloride (CCl4)–induced toxic liver fibrosis and 3,5–diethoxycarbonyl–1,4–dihydrocollidine (DDC)–induced cholestatic liver fibrosis. Germline heterozygous METTL3–deficient mice and METTL3–overexpressing THLE–2 cells were applied for loss– and gain–of–function experiments. The functional requirement for ARAF, m6A enrichment of ARAF mRNA, mitochondrial dynamics, reactive oxygen species, plasma–membrane integrity, lactate release and HSC activation were assessed using RNA interference, MeRIP–seq, omics analyses, imaging and Transwell co–culture.Results: METTL3 was increased in fibrotic human and mouse liver. Heterozygous METTL3 deficiency attenuated fibrosis in both models, whereas METTL3 overexpression enhanced profibrotic signaling and paracrine HSC activation. Mechanistically, METTL3 associated with ARAF and enhanced ARAF–ERK1/2 signaling through a mechanism not primarily explained by altered ARAF m6A enrichment. This response was accompanied by increased Drp1S616 phosphorylation, mitochondrial fission and mitochondrial superoxide–associated fluorescence. Mitochondrial oxidative stress promoted NINJ1 upregulation and NINJ1–dependent plasma–membrane integrity loss, accompanied by LDH and lactate release. Hepatocyte–derived lactate subsequently promoted HSC activation together with TGF–β1/Smad3 signaling.Conclusions: Hepatocyte METTL3 promotes liver fibrosis through a METTL3–ARAF–ERK–Drp1–NINJ1 axis linking mitochondrial stress to NINJ1–dependent lactate release and paracrine HSC activation.​

Introduction and Objectives: Liver stiffness measurements (LSMs) offer a noninvasive method for monitoring liver disease development. This study evaluated the prognostic value of different LSM trajectories in chronic hepatitis B (CHB) and compensated advanced chronic liver disease (cACLD) patients. Materials and Methods: We retrospectively analyzed 1272 CHB and cACLD patients with at least two LSMs, applied group-based trajectory modeling (GBTM) to identify distinct LSM trajectories, and used a Cox model to analyze their associations with liver-related events (LREs) and mortality risk. Results: Patients were categorized into five groups with distinct LSM trajectories: 67 (8.5 %), 13 (11 %), 36 (23.5 %), 34 (27.6 %) and 23 (25.0 %) developed LREs in Groups 1–5. The low stable trajectory (Group 3), the medium gradual decrease trajectory (Group 4) and high quickly decrease followed by increase trajectory (Group 5) had higher LREs risks than the low gradual decrease trajectory (Group 1) (adjusted HRs 2.26, 2.39, 2.67; 95 % CIs 1.50–3.40, 1.57–3.66, 1.61–4.43, respectively). Similar elevated risks were observed for hepatic decompensation, hepatocellular carcinoma (HCC), liver-related and all-cause mortality, except that there was no significant difference in the risk of HCC between Groups 4 and 1 (aHR 0.66, 0.36–1.23). When comparing Group 1 with the medium quickly decrease trajectory (Group 2), no significant differences were noted in the prognosis (P > 0.05). Notably, age over 40, high LSM, low PLT, and high total bilirubin were linked to high-risk trajectories (Groups 3–5). Conclusions: Monitoring LSM trajectories improves prognostic prediction in CHB and cACLD compared with single measurements and may guide personalized treatment strategies.

BACKGROUND:The applicability of the Agile 3+ score to patients with CHB-MASLD receiving antiviral therapy remains unexplored. Our objective was to explore the diagnostic and prognostic performances of the Agile 3+ score in patients with CHB-MASLD. METHODS:This retrospective cohort study included consecutively enrolled patients with CHB and concurrent MASLD from 2014 to 2020. In Part 1, we evaluated the performance of the Agile 3+ score in predicting advanced fibrosis. In Part 2, the Agile 3+ score was applied to a follow-up cohort to assess its correlation with liver-related events. RESULTS:Among the 2492 patients evaluated by vibration-controlled transient elastography, 103 patients with CHB and hepatic steatosis were included in the biopsy cohort, and 716 patients were included in the follow-up cohort. The Agile 3+ score had the highest AUROC of 0.916 for the prediction of advanced fibrosis, outperforming the FIB-4 score (0.845), NFS (0.838), and APRI (0.726). In predicting liver-related events (LREs), the AUROC of the Agile 3+ score was also significantly higher (0.795 at 3 years, 0.809 at 5 years, and 0.834 at 8 years) than those of the other noninvasive tests. When the recommended cutoffs (0.451 and 0.679) were applied for MASLD risk stratification, the high-risk group (HR = 13.61) and intermediate-risk group (HR = 3.53) had significantly greater risks of LREs than the low-risk group. CONCLUSION:In patients with CHB and concurrent MASLD receiving antiviral therapy, the Agile 3+ score effectively identifies advanced fibrosis and predicts LRE risk, supporting its clinical utility in this population.

Background In chronic hepatitis B patients, an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes. Methods We conducted a retrospective cohort study to compare the risk of transitioning to the Immune Active phase in patients with indeterminate chronic hepatitis B and the incidence of adverse liver outcomes (hepatocellular carcinoma and/or cirrhosis) between untreated patients with indeterminate chronic hepatitis B (at baseline and throughout follow-up) and those who received treatment, following standard AASLD 2018 guidance. Results Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated patients. Following IPTW adjustment, the 5-, 10-, and 12-year risk of transitioning to Immune Active was 11.8%, 12.3%, and 13.5% among treated patients (n=294), compared to 39.2%, 43.6%, and 44.8% among untreated patients (n=334), respectively (P<0.001) (IDDF2024-ABS-0177 Figure 1). Furthermore, the cumulative incidence of hepatocellular carcinoma and/or cirrhosis was 2.6%, 6.7%, and 6.7% among treated patients (n=294), in contrast to 10.5%, 23.9%, and 36.8% among untreated patients (n=76), respectively (P=0.004) (IDDF2024-ABS-0177 Figure 2).In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of transitioning to Immune Active (aHR 0.238, 95% CI 0.162-0.351, P<0.001) and of reducing the risk of hepatocellular carcinoma and/or cirrhosis (aHR 0.153, 95% CI 0.054 -0.434, P<0.001). Conclusions The phase of indeterminate chronic hepatitis B patients changes frequently, and antiviral therapy can reduce the risk of transitioning to Immune Active as well as the incidence of developing hepatocellular carcinoma and/or cirrhosis.

BACKGROUND AND AIMS:In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes. METHODS:We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow-up) and those who received treatment, following standard AASLD 2018 guidance. RESULTS:The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients (n = 104). For HBeAg-negative indeterminate phase patients (n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg-positive indeterminate phase patients (n = 140), it was 40.4%, 52.0%, and 55.0% (p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan-Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients (n = 294) is higher than that among treated patients (n = 76), (p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031-0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044-0.496, p = 0.002). CONCLUSION:The indeterminate phase patients had a high-risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.

Acetaminophen (APAP) stands as the predominant contributor to drug-induced liver injury (DILI), and limited options are available. β-Arrestin1 (ARRB1) is involved in numerous liver diseases. However, the role of ARRB1 in APAP-induced liver injury remained uncertain. Wild-type (WT) and ARRB1 knockout (KO) mice were injected with APAP and sacrificed at the indicated times. The histological changes, inflammation, endoplasmic reticulum (ER) stress, and apoptosis were then evaluated. Hepatic cell lines AML-12 and primary hepatocytes were used for in vitro analyses. Systemic ARRB1 -KO mice were susceptible to APAP-induced hepatotoxicity, as indicated by larger areas of centrilobular necrosis area and higher levels of ALT, AST, and inflammation level. Moreover, ARRB1 -KO mice exhibited increased ER stress (indicated by phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)) and apoptosis (indicated by cleaved caspase 3). Further rescue experiments demonstrated that the induction of apoptosis was partially mediated by ER stress. Overexpression of ARRB1 alleviated APAP-induced ER stress and apoptosis. Moreover, co-IP analysis revealed that ARRB1 directly bound to p-eIF2α and eIF2α. ARRB1 protected against APAP-induced hepatoxicity through targeting ER stress and apoptosis. ARRB1 is a prospective target for treating APAP-induced DILI. Graphical Abstract ARRB1 mitigates APAP-induced hepatotoxicity through regulating ER stress (p-eIF2α-ATF4-CHOP) and apoptosis (p-JNK and cleaved caspase 3) via binding to p-eIF-2α

Abstract Background: Acute-phase reactions (APRs) are common among people who are treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APR and ZOL efficacy remains unclear. Methods： This study was a self pre - post control study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients withan average age of 67.4±5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs , blood counts, bone turnover markers, including CTX and PINP, and bone mineral density (BMD) were collected. Results： 1) The results did not show a relationship between the APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in BMD of LS at Month 6 and Month 12 (r=0.304 P<0.05, r=0.387 P<0.01). 2) This effect was mainly mediated by changes in serum CTX (b=0.046, 95% CI [0.0010-0.0091]). 3) TheROC curve showed that when T increased by 1.95°C, the sensitivity and specificity of judging the clinically important change in LS BMD after 1 year were the best. Conclusions: In this study, we tested the hypothesis that people with elevated body T after initial ZOL treatment had greater BMD improvements and better outcomes.

Acute-phase reactions (APRs) are common among people treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APRs and ZOL efficacy remains unclear. This was a prospective observational cohort study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients with an average age of 67.4 ± 5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs, blood counts, bone turnover markers, including C-telopeptide collagen crosslinks (CTX) and N-terminal propeptide of type 1 collagen (PINP), and bone mineral density (BMD) were collected. (1) The results did not reveal a relationship between APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in the BMD of the LS at Month 12 (β = 0.279 P = 0.034). (2) This effect was mediated mainly by changes in serum CTX (b = 0.046, 95

Supplemental Methods and Materials

Evidence exists of a strong association between inflammation and a decrease in skeletal muscle function and bone mineral density (BMD); however, the specific mechanisms of these associations remain unclear. Adipokines, as key regulators of the inflammatory response, may be implicated in these processes. The objective of this study was to explore the potential correlation between adipokines, skeletal muscle function and BMD in middle-aged and elderly individuals. A comparative cross-sectional study was carried out at the Huadong Hospital Affiliated with Fudan University (Shanghai, China). A total of 460 middle-aged and elderly individuals were recruited, and 125 were enrolled in the analysis. Their biochemical indices, body composition, skeletal muscle function and BMD were measured. Bioinformatic analysis was also employed to identify potential adipokine targets linked to skeletal muscle function and BMD. To validate these targets, plasma and peripheral blood mononuclear cells (PBMCs) were harvested from these individuals and subjected to western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Individuals in this cross-sectional study were categorized into 2 groups according to their median skeletal muscle mass (SMM) (28.8 kg for males and 20.6 kg for females). Individuals with lower SMM exhibited poorer grip strength (P = 0.017), longer 5-Times-Sit-to-Stand Test (FTSST) duration (P = 0.029), lower total hip BMD (P = 0.043), lower femoral neck BMD (P = 0.011) and higher levels of inflammatory markers in comparison with individuals with higher SMM. Bioinformatics analysis identified LEP, ADIPOQ, RBP4, and DPP4 as potential adipokine targets associated with skeletal muscle function and BMD. In vitro experiments demonstrated that individuals with decreased skeletal muscle function and BMD expressed higher levels of these adipokines. Skeletal muscle function is positively correlated with BMD and negatively correlated with levels of inflammatory markers among middle-aged and elderly individuals. Those with lower skeletal muscle function and BMD tend to have a higher expression of LEP, ADIPOQ, RBP4 and DPP4.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, sug-gesting it could play an important role in hepatocellular carcino-genesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN-and HBx-induced hepa-tocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, aspar-aginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.Significance: PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.

Introduction Many Asian cohort studies have shown that nonalcoholic fatty liver disease (NAFLD), now renamed as metabolic dysfunction-associated fatty liver disease (MAFLD), increases the risk of osteoporosis, yet the effect of MAFLD on elderly patients with osteopenia (OPe) has not been reported. Objective This study aimed to explore the influence of MAFLD on the function of macrophages in patients with OPe. Methods A total of 107 elderly OPe patients with or without MAFLD who visited the Huadong Hospital Affiliated to Fudan University (Shanghai, China) between January 1st, 2021, and September 30th, 2021, were evaluated for an interviewer-assisted questionnaire, as well as clinical and biological assessments. Results Comparing two groups of elderly patients with the same bone mass level, we found that the six-minute walking distance (P = 0.012) and short physical performance battery (SPPB) score (P = 0.0029) of the elderly OPe patients with MAFLD are worse than those in OPe patients without MAFLD. Our results confirmed that the mitochondrial reactive oxygen species (mtROS) in peripheral blood of OPe patients with MAFLD was significantly higher than those without. We also observed the mitochondrial metabolism level of peripheral blood-derived macrophages in the included patients and peripheral blood macrophages in patients with MAFLD with more unbalanced mitochondrial dynamics of macrophages, more weakened mitochondrial respiratory capacity, and greater mitochondrial microstructure damage, when compared with the elderly patients without MAFLD. Conclusions To conclude, our data revealed that MAFLD itself may aggravate the inflammatory state in elderly OPe people due to mitochondrial homeostasis imbalance of peripheral blood macrophages. Damaged monocyte-macrophages might trigger attenuation of the walking ability of OPe patients.

目的 探讨中医综合疗法治疗老年膝骨关节炎(KOA)的疗效.方法 2019年9月—2021年12月,募集复旦大学附属华东医院伤外科收治的老年KOA患者122例.通过随机数字表法将患者分为观察组(n=61)和对照组(n=61),观察组以中医综合疗法(芪防膝痹方、华伤I号熨疗方和理筋整膝五步法)治疗;对照组采用西医综合疗法(塞来昔布、湿热袋敷疗和关节松动术)治疗,疗程4周.治疗前、治疗4周后,比较2组的视觉模拟评分(VAS)、西安大略和麦克马斯特大学骨关节炎指数(WOMAC)及起立行走计时(TUG),并比较不良反应的发生率.结果 与治疗前比较,治疗后2组VAS评分降低(P<0.001),TUG减少(P<0.001),WOMAC疼痛、僵硬和关节功能评分均降低(P<0.001).2组VAS(P<0.001)、TUG(P=0.024)、WOMAC疼痛(P=0.009)和WOMAC关节功能(P=0.010)评分治疗前后的差值差异有统计学意义.2组不良反应发生率差异无统计学意义(χ2=0.000,P=1.000).结论 中医综合疗法能一定程度上减轻患者的疼痛,改善患者的关节活动功能.

Sarcopenia is an age-related systemic disease characterized by skeletal muscle aging that generally severely affects the quality of life of elderly patients. Metabolomics analysis is a powerful tool for qualitatively and quantitatively characterizing the small molecule metabolomics of various biological matrices in order to clarify all key scientific problems concerning cell metabolism. The discovery of optimal therapy requires a thorough understanding of the cellular metabolic mechanism of skeletal muscle aging. In this review, the relationship between skeletal muscle mitochondria, amino acid, vitamin, lipid, adipokines, intestinal microbiota and vascular microenvironment has been separately reviewed from the perspective of metabolomics, and a new therapeutic direction has been suggested.

Aerobic glycolysis has been recognized as one of the growth-promoting metabolic alterations of cancer cells. Emerging evidence indicates that nuclear factor κB (NF-κB) plays significant roles in metabolic adaptation in normal cells and cancer cells. However, whether and how NF-κB regulates metabolic reprogramming in hepatocellular carcinoma (HCC), specifically hepatitis B virus X protein (HBx)-initiated HCC, has not been determined. A dataset of the HCC cohort from the TCGA database was used to analyse the expression of NF-κB family members. Expression of NF-κBp65 and phosphorylation of NF-κBp65 (p-p65) were detected in liver tissues from HBV-related HCC patients and normal controls. A newly established HBx+/+/NF-κBp65f/f and HBx+/+/NF-κBp65Δhepa spontaneous HCC mouse model was used to investigate the effects of NF-κBp65 on HBx-initiated hepatocarcinogenesis. Whether and how NF-κBp65 is involved in aerobic glycolysis induced by HBx in hepatocellular carcinogenesis were analysed in vitro and in vivo. NF-κBp65 was upregulated in HBV-related HCC, and HBx induced NF-κBp65 upregulation and phosphorylation in vivo and in vitro. Hepatocyte-specific NF-κBp65 deficiency remarkably decreased HBx-initiated spontaneous HCC incidence in HBx-TG mice. Mechanistically, HBx induced aerobic glycolysis by activating NF-κBp65/hexokinase 2 (HK2) signalling in spontaneous hepatocarcinogenesis, and overproduced lactate significantly promoted HCC cell pernicious proliferation via the PI3K (phosphatidylinositide 3-kinase)/Akt pathway in hepatocarcinogenesis. The data elucidate that NF-κBp65 plays a pivotal role in HBx-initiated spontaneous HCC, which depends on hyperactive NF-κBp65/HK2-mediated aerobic glycolysis to activate PI3K/Akt signalling. Thus, phosphorylation of NF-κBp65 will be a potential therapeutic target for HBV-related HCC.

Abstract BackgroundWith the increasing number of HCC patients, it is necessary to accurately predicting the prognosis of these patients. Ferroptosis has been confirmed to be closely related to HCC progression. However, there is still a challenge in predicting the survival of HCC patients through ferroptosis-related genes.MethodThe RNA-seq data and corresponding clinical data of HCC from TCGA database were downloaded to establish a prognosis model, and data of ICGC and GSE14520 as the validation set. The risk score was constructed with 5 genes identified by univariate and LASSO Cox regression analysis. Then, risk score, TNM stage and cirrhosis were included to construct a nomogram, through univariate and multivariate Cox regression analysis.Results5 genes were identified from 70 ferroptosis-related DEGs to construct a gene signature to predict HCC patient survival from TCGA cohort. PCA and heatmap results show that there are obvious differences in patients with different score groups. Then, we included risk score, TNM stage and cirrhosis to construct a nomogram to further predict the overall survival of the patients. Survival analysis indicates that overall survival of the low- risk group is significantly higher than that of the high-risk group. Similarly, the data in the GSE14520 cohort also confirmed good performance for the nomogram. Furthermore, KEGG and GO functional enrichment analyses indicates the difference in overall survival between groups is closely related to immune-related pathways. Finally, through analyzing the immune status of all patients, we found that compared with patients in the low-risk group, “Macrophages M0”, “T cells CD8”, and “T cells regulatory” of the high-risk group were significantly higher.ConclusionThe nomogram based on ferroptosis-related genes has a good performance for the prognosis of HCC patients. The model may provide a reference for evaluation of HCC patients by targeting ferroptosis.

目的 探讨唾液中可作为协诊早期肝细胞癌的lncRNA标志物.方法 首先利用Agilent基因芯片技术,在3份正常肝组织和3份肝细胞癌组织中挑选表达差异最明显的一种lncRNA.然后扩大样本量,利用定量PCR技术检测这种lncRNA在肝细胞癌和对照正常组织、血浆和唾液中的表达水平.结果 lncRNA-JAKMIP2-1:1在肝细胞癌患者的癌组织、血浆和唾液中均明显升高(P均<0.05),在肝细胞癌患者的癌组织、血浆和唾液中3种样本中的表达显示两两呈正相关,同时lnc-JAKMIP2-1:1在早期(Ⅰ/Ⅱ期)肝细胞癌患者的唾液中表达就已经明显升高,在接受手术后,其表达又明显下降.通过受试者工作特征曲线分析,唾液lnc-JAKMIP2-1:1诊断早期肝细胞癌的灵敏度为100％,特异度为86％.结论 唾液lnc-JAKMIP2-1:1是协诊早期肝细胞癌的理想标志物.

Acute liver injury (ALI) caused by multiple inflammatory responses is a monocyte-/macrophage-mediated liver injury that is associated with high morbidity and mortality. Liver macrophage activation is a vital event that triggers ALI. However, the mechanism of liver macrophage activation has not been fully elucidated. This study examined the role of β-arrestin1 (ARRB1) in wild-type (WT) and ARRB1- knockout ( ARRB1 -KO) mouse models of ALI induced by lipopolysaccharide (LPS), and ARRB1 -KO mice exhibited more severe inflammatory injury and liver macrophage activation compared to WT mice. We found that LPS treatment reduced the expression level of ARRB1 in Raw264.7 and THP-1 cell lines, and mouse primary hepatic macrophages. Overexpression of ARRB1 in Raw264.7 and THP-1 cell lines significantly attenuated LPS-induced liver macrophage activation, such as transformation in cell morphology and enhanced expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), while downregulation of ARRB1 by small interfering RNA and ARRB1 deficiency in primary hepatic macrophages both aggravated macrophage activation. Moreover, overexpression of ARRB1 suppressed LPS-induced endoplasmic reticulum (ER) stress in liver macrophages, and inhibition of ER stress impeded excessive hepatic macrophage activation induced by downregulation of ARRB1. Our data demonstrate that ARRB1 relieves LPS-induced ALI through the ER stress pathway to regulate hepatic macrophage activation and that ARRB1 may be a potential therapeutic target for ALI.