Correction: Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

[This corrects the article DOI: 10.1371/journal.ppat.1006773.].

The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.

Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.

Correction: Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

[This corrects the article DOI: 10.1371/journal.ppat.1006773.].

Amplitude reduction of autonomic nerve function is correlated with ablation lesion quality in patients with paroxysmal atrial fibrillation.

OBJECTIVE: Circumferential pulmonary vein isolation (CPVI) is a common procedure that is performed on patients with atrial fibrillation (AF). However, AF may recur in some patients after treatment. This study assesses the association between autonomic modulation and late recurrence after CPVI and between autonomic modulation and ablation lesion quality. METHODS: We prospectively enrolled 72 patients with paroxysmal AF who underwent CPVI from January 2017 to January 2018. Pre- and post-ablation 24 h electrocardiograms were performed to document heart rate variability (HRV), which represents cardiac autonomic function. The intraablation force-time integral (FTI) was used to indicate the extent of ablation injury. Patients were followed up for 12 months after the procedure and cases of AF recurrence were recorded. RESULTS: Changes in HRV decreased after the procedure, which was correlated with FTI (ΔSDNN: r = -0.26, P = 0.03; ΔrMMSD: r = -0.28, P = 0.02; ΔlnHF: r = -0.22, P = 0.04; ΔLnLF: r = -0.29, P = 0.01). Patients without AF recurrence had more pronounced ΔLF (-21.84 ± 33.21% vs. -8.68 ± 34.59%, P = 0.01) and ΔHF (-17.26 ± 16.61% vs. -1.28 ± 9.81%, P = 0.01) than patients with recurrence. Multivariate regression analysis showed that both ΔLF (HR: 1.07, P = 0.04) and ΔHF (HR: 1.11, P = 0.01) were associated with AF recurrence. After adjusting for FTI, ΔLF was no longer associated with AF recurrence (HR: 1.05, P = 0.10). ΔHF remained associated with AF recurrence (HR: 1.08, P = 0.03), but the correlation coefficient was decreased (HR: 1.08, P = 0.03). CONCLUSION: Decreased autonomic nerve function is a valid predictor of AF recurrence and is indicated by the extent of ablation injury, which is independently associated with AF recurrence after CPVI.

Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses. We have found that LSD1 is recruited to demethylate IFITM3 at position K88 under IFNα treatment. However, infection by either Vesicular Stomatitis Virus (VSV) or Influenza A Virus (IAV) triggers methylation of IFITM3 by promoting its disassociation from LSD1. Accordingly, inhibition of the enzymatic activity of LSD1 by Trans-2-phenylcyclopropylamine hydrochloride (TCP) increases IFITM3 monomethylation which leads to more severe disease outcomes in IAV-infected mice. In summary, our findings highlight the opposite role of LSD1 in fighting RNA viruses comparing to DNA viruses infection. Our data suggest that the demethylation of IFITM3 by LSD1 is beneficial for the host to fight against RNA virus infection.

Chitinase 3-like-1 promotes intrahepatic activation of coagulation through induction of tissue factor in mice.

Coagulation is a critical component in the progression of liver disease. Identification of key molecules involved in the intrahepatic activation of coagulation (IAOC) will be instrumental in the development of effective therapies against liver disease. Using a mouse model of concanavalin A (ConA)-induced hepatitis, in which IAOC plays an essential role in causing liver injury, we uncovered a procoagulant function of chitinase 3-like 1 (Chi3l1). Chi3l1 expression is dramatically elevated after ConA challenge, which is dependent on ConA-induced T cell activation and the resulting interferon γ and tumor necrosis factor α productions. Compared with wild-type mice, Chi3l1-/- mice show less IAOC, reduced tissue factor (TF) expression, and attenuated liver injury. Reconstituting Chi3l1-/- mice with recombinant TF triggers IAOC and augments liver injury. CONCLUSION: Our data demonstrate that Chi3l1, through induction of TF via mitogen-activated protein kinase activation, promotes IAOC and tissue injury. (Hepatology 2018;67:2384-2396).

Human cytomegalovirus exploits interferon-induced transmembrane proteins to facilitate morphogenesis of the virion assembly compartment.

UNLABELLED: Recently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication. IMPORTANCE: HCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we identified a new function of IFITMs during the very late stage of virus replication, i.e., virion assembly. Virus entry and assembly both involve vesicle transport and membrane fusion; thus, a common biochemical activity of IFITMs is likely to be involved. Therefore, our findings may provide a new platform for dissecting the molecular mechanism of action of IFITMs during the blocking or enhancement of virus infection, which are under intense investigation in this field.

Negative regulation of interferon-induced transmembrane protein 3 by SET7-mediated lysine monomethylation.

Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels. These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases.

Blood pressure among children and adolescents with normal weight but large waist circumference in Shandong, China.

UNLABELLED: The present study examined the blood pressure (BP) characteristics of normal weight children and adolescents with a large waist circumference (WC) in a large population in Shandong, China. A total of 38,826 students (19,460 boys and 19,366 girls) aged 7-17 years participated in this study. Height, weight, WC, and BP of all subjects were measured. Normal weight was defined by the international cutoffs of body mass index; central obesity was defined as WC ≥ 90th percentile; relatively high BP status was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ 95th percentile for age and gender. And 5.06 and 8.19 % of the normal weight boys and girls had central obesity. The Z-scores of SBP, DBP and the prevalence of relatively high BP for both boys and girls were all significantly higher in the normal weight with central obesity groups than in the normal weight with normal WC groups. CONCLUSION: These observations highlight that normal weight children and adolescents with central obesity might have an increased risk of elevated BP.

Protective effects of apocynin on atrial electrical remodeling and oxidative stress in a rabbit rapid atrial pacing model.

It has been proposed that apocynin might be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to investigate the effects of apocynin on atrial electrical remodeling and oxidative stress promoted by rapid atrial pacing (RAP) in rabbits. New Zealand white rabbits were subjected to RAP with or without apocynin treatment. Serial electrophysiological studies (EPS) were performed at baseline and every half hour after RAP onset. Superoxide dismutase (SOD) and lactate dehydrogenase (LDH) activities and Ca²âº content in tissue homogenates of both atria were assayed after EPS. In the RAP group but not in the sham-operated and RAP with apocynin groups, atrial effective refractory periods (AERPs) at cycle length of 200 and 150 ms shortened most clearly by 20.8 ± 10.2 ms at 3 h (P < 0.001) and by 12.8 ± 11.1 ms at 2 h (P < 0.05) respectively, and AERP rate adaptation decreased to minus values. Higher AF inducibility (66.7%) and longer AF duration (an average of 37.8 min) were presented in the RAP group. Compared with the other groups, SOD activity was lower, and LDH activity and Ca²âº content were higher in the RAP group. Similar differences were not found between the sham-operated and the RAP with apocynin treatment groups. These data show that apocynin attenuates the development of atrial electrical remodeling in a short period of 3-hour RAP, and reduces RAP-mediated inducibility and duration of AF in this model.

Transcriptomic analysis of epicardial adipose tissue reveals the potential crosstalk genes and immune relationship between type 2 diabetes mellitus and atrial fibrillation.

BACKGROUND: The complex relationship between atrial fibrillation (AF) and type 2 diabetes mellitus (T2DM) suggests a potential role for epicardial adipose tissue (EAT) that requires further investigation. This study employs bioinformatics and experimental approaches to clarify EAT's role in linking T2DM and AF, aiming to unravel the biological mechanisms involved. METHOD: Bioinformatics analysis initially identified common differentially expressed genes (DEGs) in EAT from T2DM and AF datasets. Pathway enrichment and network analyses were then performed to determine the biological significance and network connections of these DEGs. Hub genes were identified through six CytoHubba algorithms and subsequently validated biologically, with further in-depth analyses confirming their roles and interactions. Experimentally, db/db mice were utilized to establish a T2DM model. AF induction was executed via programmed transesophageal electrical stimulation and burst pacing, focusing on comparing the incidence and duration of AF. Frozen sections and Hematoxylin and Eosin (H&E) staining illuminated the structures of the heart and EAT. Moreover, quantitative PCR (qPCR) measured the expression of hub genes. RESULTS: The study identified 106 DEGs in EAT from T2DM and AF datasets, underscoring significant pathways in energy metabolism and immune regulation. Three hub genes, CEBPZ, PAK1IP1, and BCCIP, emerged as pivotal in this context. In db/db mice, a marked predisposition towards AF induction and extended duration was observed, with HE staining verifying the presence of EAT. Additionally, qPCR validated significant changes in hub genes expression in db/db mice EAT. In-depth analysis identified 299 miRNAs and 33 TFs as potential regulators, notably GRHL1 and MYC. GeneMANIA analysis highlighted the hub genes' critical roles in stress responses and leukocyte differentiation, while immune profile correlations highlighted their impact on mast cells and neutrophils, emphasizing the genes' significant influence on immune regulation within the context of T2DM and AF. CONCLUSION: This investigation reveals the molecular links between T2DM and AF with a focus on EAT. Targeting these pathways, especially EAT-related ones, may enable personalized treatments and improved outcomes.

The role of 1-h physical activity every day in preventing obesity in adolescents in Shandong, China.

Several studies have reported that physical inactivity and sedentary lifestyle are associated with being overweight and obese in children and adults. A new policy of 1-h physical activity (PA) every day was released by the Chinese government. The present study examined the role of 1-h PA every day in preventing obesity in adolescents in Shandong, China. A total of 29,030 students (14,578 boys and 14,452 girls) aged 10-18 years participated in this study. Height, weight, waist circumference (WC), and skinfold thickness (SFT) of all subjects were measured; body mass index (BMI) of adolescents was calculated from their height and weight, and the prevalence of overweight and obesity was obtained according to the International Obesity Task Force cutoffs. All subjects were divided into two groups. Group 1 had a PA of more than 1 h/day while group 2 had less than 1 h/day. Comparisons of BMI, WC, SFT, and prevalences of overweight and obesity between the two groups were made. The overall percentages of students in group 1 were 34.29 % in boys and 30.15 % in girls. The prevalences of overweight and obesity for both boys and girls were all significantly lower in group 1 than in group 2 in all age categories. In conclusion, 1-h PA every day has a beneficial effect in preventing obesity in adolescents in Shandong, China. These observations highlight the importance of PA in the prevention of overweight and obesity in adolescents.

Distributions of waist circumference and waist-to-height ratio for children and adolescents in Shandong, China.

UNLABELLED: Waist circumference (WC) and waist-to-height ratio (WHtR) are useful tools which can help to identify abdominal obesity among the childhood and adolescent populations. This study assessed the distributions of WC and WHtR for Shandong children and adolescents and compared them with those from other countries and regions. Data for this study were obtained from a large cross-sectional survey of schoolchildren carried out in 2010. A total of 42,296 students (21,218 boys and 21,078 girls) aged 7-18 years participated in this study. Height and WC of all subjects were measured and WHtR was calculated. Central obesity was defined as WC ≥ 90th percentile and a WHtR ≥ 0.5, respectively. Shandong children and adolescents had a high WC level, with the 50th percentiles of WC for children and adolescents aged 7 to 18 years in Shandong is above the reference values for Chinese children and adolescents by 1.3-3.1 cm for boys and 1.2-2.0 cm for girls, respectively. The WC levels in Shandong boys and girls were higher than those from Hong Kong, Malaysian, and Turkish. Overall, 20.20 and 16.57 % of boys and girls had a WC ≥90th percentile, 15.73 and 7.38 % of boys and girls had a WHtR ≥0.5. CONCLUSION: The prevalence of central obesity among children and adolescents has become a serious public health problem, which would arouse special attention.

Comparison on physical activity among adolescents with different weight status in Shandong, China.

The present study examined the prevalence of underweight, overweight and obesity among adolescents and compared the attitudes and behaviors of physical activity (PA) among adolescents with different weight status in Shandong, China. A total of 19 523 students (9784 boys and 9739 girls) aged 13-18 years participated in this study. Height and weight of all subjects were measured, body mass index of adolescents was calculated from their height and weight, and the prevalence of overweight and obesity were obtained according to the International Obesity Task Force cut-offs. The prevalence of underweight were also obtained by the international cut-offs. PA status was assessed by a standardized questionnaire. The overall prevalence rates of underweight, overweight and obesity were 2.0, 13.9 and 4.7% in boys and 3.3, 8.3 and 1.2% in girls, respectively. Overweight/obese adolescents had a poor PA status compared with underweight/normal-weight adolescents. These observations highlight the importance of PA in the prevention of overweight and obesity in adolescents.

The mediating effect of mindfulness on demoralization syndrome and quality of life of thyroid cancer patients: A correlational study.

Demoralization syndrome is prevalence among cancer patients in China. However, little research has examined how demoralization syndrome is associated with quality of life (QOL). The aims of this study were to investigate the relationship between mindfulness state, demoralization syndrome and QOL of thyroid cancer patients, and explore the mediating effect of mindfulness on demoralization syndrome and QOL. A correlational cross-sectional study was performed using an online questionnaire. The study was conducted from July to October 2022 among 310 thyroid cancer patients. General information questionnaire, the Demoralization Scale, Five Facet Mindfulness Questionnaire, short form health survey questionnaire were used for investigation. Calculations were performed using SPSS Statistics, version 25. Descriptive statistics, correlation, and process plug-in mediation effect analyses were used to analyze the data. A total of 310 valid questionnaires were finally recovered. The Five Facet Mindfulness Questionnaire score of 310 patients was (120.80 ± 16.57), Demoralization Scale score was (12.49 ± 4.73), short form health survey questionnaire score was (146.15 ± 28.46). Mindfulness played a partial mediating role between demoralization syndrome and QOL of thyroid cancer patients, and the mediating effect accounted for 68.57% of the total effect. Demoralization syndrome can influence QOL through mindfulness state. Measures are needed to increase the QOL of thyroid cancer patients by developing mindfulness programs to decrease their demoralization syndrome.

ScRNA-seq and ST-seq in liver research.

Spatial transcriptomics, which combine gene expression data with spatial information, has quickly expanded in recent years. With application of this method in liver research, our knowledge about liver development, regeneration, and diseases have been greatly improved. While this field is moving forward, a variety of problems still need to be addressed, including sensitivity, limited capacity to obtain exact single-cell information, data processing methods, as well as others. Methods like single-cell RNA sequencing (scRNA-seq) are usually used together with spatial transcriptome sequencing (ST-seq) to clarify cell-specific gene expression. In this review, we explore how advances of scRNA-seq and ST-seq, especially ST-seq, will pave the way to new opportunities to investigate fundamental questions in liver research. Finally, we will discuss the strengths, limitations, and future perspectives of ST-seq in liver research.

A novel humanized Chi3l1 blocking antibody attenuates acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both in vitro and in vivo biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5ß loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI in vivo. Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.

Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment.

The prevalence of type 2 diabetes is associated with inflammatory bowels diseases, nonalcoholic steatohepatitis and even a spectrum of cancer such as colon cancer and liver cancer, resulting in a substantial healthcare burden on our society. Autophagy is a key regulator in metabolic homeostasis such as lipid metabolism, energy management and the balance of cellular mineral substances. Mitophagy is selective autophagy for clearing the damaged mitochondria and dysfunctional mitochondria. A myriad of evidence has demonstrated a major role of mitophagy in the regulation of type 2 diabetes and metabolic homeostasis. It is well established that defective mitophagy has been linked to the development of insulin resistance. Moreover, insulin resistance is further progressed to various diseases such as nephropathy, retinopathy and cardiovascular diseases. Concordantly, restoration of mitophagy will be a reliable and therapeutic target for type 2 diabetes. Recently, various phytochemicals have been proved to prevent dysfunctions of ß-cells by mitophagy inductions during diabetes developments. In agreement with the above phenomenon, mitophagy inducers should be warranted as potential and novel therapeutic agents for treating diabetes. This review focuses on the role of mitophagy in type 2 diabetes relevant diseases and the pharmacological basis and therapeutic potential of autophagy regulators in type 2 diabetes.

[Dynamic comparisons of epicardial electrograms between the left atrium and pulmonary veins in atrial fibrillation in goat model].

Objective: To compare epicardial electrograms between the left atrium (LA) and pulmonary veins (PVs) dynamically at development of persistent atrial fibrillation(AF) in goats PVs. Methods: Ten female goats were instrumented with electrodes at the LA and left side PV. Sustained AF (＞24 h) was induced in the goat by rapid intermittent left atrial pacing for(9.5±2.3)days at a pacing interval of 20 ms for 1 s with a maximum output of 6.0 V, followed by a 2-s period without pacing. Characteristics of PVs and LA epicardial electrograms were analyzed in the development of AF. Results: With prolonged stimulation, the duration of AF was prolonged, complex fractionated atrial electrograms(CFAEs) in LA and was increased gradually, PVs had more CFAEs than LA all the time. When induced AF lasted for more than 24 h, CFAEs in PVs became sustained approximately (2.7%±3.6% vs 92.6%±6.4%, at onset of AF vs AF lasted for more than 24 h, P＜0.05), and the ratio of CFAEs in PVs was more than that in LA (92.6%±6.4% vs 72.8%±5.3%, P＜0.05). Conclusion: The epicardial CFAEs are in specific area, which increase along with electrical remodeling. The epicardial CFAEs may play an important role in the maintenance of AF in this model.

Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment.

Background: Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. Methods: Mice were fasted overnight before intraperitoneally (i.p.) injected with APAP at a dose of 210 mg/kg for male mice and 325 mg/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of α-chitinase 3-like-1 (α-Chi3l1) on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed. Results: The present study unveiled a critical role of Chi3l1 in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chil1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of Cd44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chil1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chil1-/- mice, but not in Cd44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Conclusions: We uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI. Funding: ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042-20030616). CJ received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work were supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Acetaminophen, also called paracetamol outside the United States, is a commonly used painkiller, with over 50 million people in the United States taking the drug weekly. While paracetamol is safe at standard doses, overdose can cause acute liver failure, which leads to 30,000 patients being admitted to emergency care in the United States each year. There is only one approved antidote to overdoses, which becomes significantly less effective if its application is delayed by more than a few hours. This has incentivized research into identify new drug targets that could lead to additional treatment options. Acetaminophen overdose triggers blood clotting and inflammation, contributing to liver injury. It also causes a decrease in cells called platelets circulating in the blood, which has been observed in both mice and humans. In mice, this occurs because platelets accumulate in the liver. Removing these excess cells appears to reduce the severity of the damage caused by acetaminophen, but it remains unclear how the drug triggers their accumulation in the liver. In 2018, researchers showed that a protein called Chi3l1 plays an important role in another form of liver damage. Shan et al. ­ including many of the researchers involved in the 2018 study ­ have examined whether the protein also contributes to acetaminophen damage in the liver. Shan et al. showed that mice lacking the gene that codes for Chi3l1 developed less severe liver injury and had fewer platelets in the liver following acetaminophen overdose. They also found that human patients with acute liver failure due to acetaminophen had high levels of Chi3l1 and significant accumulation of platelets in the liver. To test whether damage could be prevented, Shan et al. used antibodies to neutralize Chi3l1 in mice after giving them an acetaminophen overdose. This reduced platelet accumulation in the liver and the associated damage. These findings suggest that targeting Chi3l1 may be an effective strategy to prevent liver damage caused by acetaminophen overdose. Further research could help develop new treatments for acetaminophen-induced liver injury and perhaps other liver conditions.