Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2.

Background: Gliomas are the most prevalent primary malignant tumors of the central nervous system. Our previous study showed that miR-204-5p is a tumor suppressor gene in glioma. Bioinformatic analyses suggest that long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) is a potential target gene of miR-204-5p. Methods: We analyzed the expression of XIST and miR-204-5p in glioma tissues and the correlation with glioma grade. A series of in vitro experiments were carried out to elucidate the role of XIST in glioma progression. A mouse xenograft model was established to detect whether knockdown of XIST can inhibit glioma growth. A luciferase assay was performed to determine whether XIST can bind to miR-204-5p and the binding specificity. Cells stably expressing shXIST or shNC were transfected with anti-miR-204-5p or anti-miR-204-5p-NC to evaluate whether XIST mediates the tumor-suppressive effects of miR-204-5p. Results: XIST was upregulated in glioma tissues compared with normal brain tissues (NBTs), while miR-204-5p expression was significantly decreased in glioma tissues compared with NBTs. Both XIST and miR-204-5p expression levels were clearly related to glioma grade, and the expression of XIST was obviously negatively correlated with miR-204-5p expression. Knockdown of XIST inhibited glioma cell proliferation, migration, and invasion, promoted apoptosis of glioma cells, inhibited tumor growth and increased the survival time in nude mice. miR-204-5p could directly bind to XIST and negatively regulate XIST expression. XIST mediated glioma progression by targeting miR-204-5p in glioma cells. XIST crosstalk with miR-204-5p regulated Bcl-2 expression to promote apoptosis. Conclusion: Our results provide evidence that XIST, miR-204-5p and Bcl-2 form a regulatory axis that controls glioma progression and can serve as a potential therapeutic target for glioma.

Myocardial infarction (MI) is a major cause of death worldwide. Although percutaneous coronary intervention and coronary artery bypass grafting can prolong life, cardiac damage persists. In particular, cardiomyocytes have no regenerative capacity. Mesenchymal stem cells (MSCs) are attractive candidates for the treatment of MI. The manner by which MSCs exert a beneficial effect upon injured cells is a source of continued study.

Infectious diseases cause tremendous financial losses in the pork industry, emphasizing the importance of disease resilience, which is the ability of an animal to maintain performance under disease. Previously, a natural polymicrobial disease challenge model was established, in which pigs were challenged in the late nursery phase by multiple pathogens to maximize expression of genetic differences in disease resilience. Genetic analysis found that performance traits in this model, including growth rate, feed and water intake, and carcass traits, as well as clinical disease phenotypes, were heritable and could be selected for to increase disease resilience of pigs. The objectives of the current study were to identify genomic regions that are associated with disease resilience in this model, using genome-wide association studies and fine-mapping methods, and to use gene set enrichment analyses to determine whether genomic regions associated with disease resilience are enriched for previously published quantitative trait loci, functional pathways, and differentially expressed genes subject to physiological states. Multiple quantitative trait loci were detected for all recorded performance and clinical disease traits. The major histocompatibility complex region was found to explain substantial genetic variance for multiple traits, including for growth rate in the late nursery (12.8%) and finisher (2.7%), for several clinical disease traits (up to 2.7%), and for several feeding and drinking traits (up to 4%). Further fine mapping identified 4 quantitative trait loci in the major histocompatibility complex region for growth rate in the late nursery that spanned the subregions for class I, II, and III, with 1 single-nucleotide polymorphism in the major histocompatibility complex class I subregion capturing the largest effects, explaining 0.8-27.1% of genetic variance for growth rate and for multiple clinical disease traits. This single-nucleotide polymorphism was located in the enhancer of TRIM39 gene, which is involved in innate immune response. The major histocompatibility complex region was pleiotropic for growth rate in the late nursery and finisher, and for treatment and mortality rates. Growth rate in the late nursery showed strong negative genetic correlations in the major histocompatibility complex region with treatment or mortality rates (-0.62 to -0.85) and a strong positive genetic correlation with growth rate in the finisher (0.79). Gene set enrichment analyses found genomic regions associated with resilience phenotypes to be enriched for previously identified disease susceptibility and immune capacity quantitative trait loci, for genes that were differentially expressed following bacterial or virus infection and immune response, and for gene ontology terms related to immune and inflammatory response. In conclusion, the major histocompatibility complex and other quantitative trait loci that harbor immune-related genes were identified to be associated with disease resilience traits in a large-scale natural polymicrobial disease challenge. The major histocompatibility complex region was pleiotropic for growth rate under challenge and for clinical disease traits. Four quantitative trait loci were identified across the class I, II, and III subregions of the major histocompatibility complex for nursery growth rate under challenge, with 1 single-nucleotide polymorphism in the major histocompatibility complex class I subregion capturing the largest effects. The major histocompatibility complex and other quantitative trait loci identified play an important role in host response to infectious diseases and can be incorporated in selection to improve disease resilience, in particular the identified single-nucleotide polymorphism in the major histocompatibility complex class I subregion.

Acute myocardial infarction (AMI), one of the most severe and fatal cardiovascular diseases, remains the main cause of mortality and morbidity worldwide. The objective of this study is to investigate the potential biomarkers for AMI based on bioinformatics analysis. A total of 2102 differentially expressed genes (DEGs) were screened out from the data obtained from the gene expression omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) explored the co-expression network of DEGs and determined the key module. The brown module was selected as the key one correlated with AMI. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that genes in the brown module were mainly enriched in 'ribosomal subunit' and 'Ribosome'. Gene Set Enrichment Analysis revealed that 'TNFA_SIGNALING_VIA_NFKB' was remarkably enriched in AMI. Based on the protein-protein interaction network, ribosomal protein L9 (RPL9) and ribosomal protein L26 (RPL26) were identified as the hub genes. Additionally, the polymerase chain reaction (PCR) results indicated that the expression levels of RPL9 and RPL26 were both downregulated in AMI patients compared with controls, in accordance with the bioinformatics analysis. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of AMI.

Nerve transfer is an important clinical surgical procedure for nerve repair by the coaptation of a healthy donor nerve to an injured nerve. Usually, nerve transfer is performed in an end-to-end manner, which will lead to functional loss of the donor nerve. In this study, we aimed to evaluate the efficacy of 3D-printed branch nerve conduits in nerve transfer.

Consistent high-risk human papillomavirus (HPV) infection leads to various malignant cancers. Autophagy can promote cancer progression by helping cancer cells survive under stress or induce oncogenic effects when mutations or abnormalities occur. Mitogen activated protein kinases (MAPKs) can transduce various external or intrinsic stimuli into cellular responses, including autophagy, and dual-specificity phosphates (DUSPs) contribute to the direct regulation of MAPK activities. Previously, we showed that expression of DUSP5 was repressed in HPV16 E7-expressing normal human epidermal keratinocytes (NHEKs). Here we show that clinical HPV16 E7-positive precancerous and cancerous tissues also demonstrate low DUSP5 levels compared with control tissues, indicating that the inverse correlation between HPV16 E7 and DUSP5 is clinically relevant. We furthermore investigated the autophagy response in both DUSP5-deficient and HPV16 E7-expressing NHEKs. Confocal microscopy and Western analysis showed induction of LC3-II levels, autophagosome formation and autophagy fluxes in DUSP5-deficient NHEKs. Furthermore, Western analysis demonstrated specific induction of phosphorylated ERK in DUSP5-deficient and HPV16 E7-expressing NHEKs, indicating that HPV16 E7-mediated repression of DUSP5 results in induced MAPK/ERK signaling. Finally, phosphorylated mTOR and ULK (S757) were reduced in DUSP5-deficient NHEKs, while phosphorylated ULK (S555) and AMPK were increased, thereby inducing canonical autophagy through the mTOR and AMPK pathways. In conclusion, our results demonstrate that HPV16 E7 expression reduces DUSP5 levels, which in turn results in active MAPK/ERK signaling and induction of canonical autophagy through mTOR and MAPK regulation. Given its demonstrated inverse correlation with clinical cancerous tissues, DUSP5 may serve as a potential therapeutic target for cervical cancer.

Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.

The persistent infection of high-risk human papillomavirus (HPV) is one of the most common causes of cervical cancer worldwide, and HPV type 58 is the third most common HPV type in eastern Asia. The E7 oncoprotein is constitutively expressed in HPV58-associated cervical cancer cells and plays a key role during tumorigenesis. To study the biological function of HPV58 E7 and to characterize E7 protein-host cell interactions, we cloned the human HPV58 E7 gene and produced specific E7 antibodies. The HPV58 E7 gene was cloned into a prokaryotic expression vector, pGEX-4T2. The recombinant plasmid pGEX-4T2-(HPV58-E7) was transformed into Escherichia coli DH5α and expressed as a fusion protein containing a GST tag. After purification and removal of the GST affinity tag, the E7 protein was used as an antigen for the production of antiserum in rabbits. The specificity of the purified HPV58 E7 antibody was detected by western blotting, immunofluorescence and immunohistochemistry analysis. These methods demonstrated that the polyclonal antibody could specifically recognize the endogenous and the recombinant HPV58 E7 proteins. Immunohistochemistry analysis indicated that the E7 protein was localized in the nucleus of cervical cancer cells.

This study aims at characterizing the asymptotic behavior of genomic prediction R2 as the size of the reference population increases for common or rare QTL alleles through simulations. Haplotypes derived from whole-genome sequence of 85 Caucasian individuals from the 1,000 Genomes Project were used to simulate random mating in a population of 10,000 individuals for at least 100 generations to create the LD structure in humans for a large number of individuals. To reduce computational demands, only SNPs within a 0.1M region of each of the first 5 chromosomes were used in simulations, and therefore, the total genome length simulated was 0.5M. When the genome length is 30M, to get the same genomic prediction R2 as with a 0.5M genome would require a reference population 60 fold larger. Three scenarios were considered varying in minor allele frequency distributions of markers and QTL, for h2 = 0.8 resembling height in humans. Total number of markers was 4,200 and QTL were 70 for each scenario. In this study, we considered the prediction accuracy in terms of an estimability problem, and thereby provided an upper bound for reliability of prediction, and thus, for prediction R2. Genomic prediction methods GBLUP, BayesB and BayesC were compared. Our results imply that for human height variable selection methods BayesB and BayesC applied to a 30M genome have no advantage over GBLUP when the size of reference population was small (<6,000 individuals), but are superior as more individuals are included in the reference population. All methods become asymptotically equivalent in terms of prediction R2, which approaches genomic heritability when the size of the reference population reaches 480,000 individuals.

In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated an Uhrf1 knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygous Uhrf1 KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences. In vitro UHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications. We also show that the nucleosome positioning affects the binding of methylated DNA by UHRF1. Thus, while our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.

Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer.

Antibiotic-resistant bacteria have become a major issue due to the long-term use and abuse of antibiotics in treatments in clinics. The combination therapy of antibiotics and silver (Ag) nanoparticles is an effective way of both enhancing the antibacterial effect and decreasing the usage of antibiotics. Although the method has been proved to be effective in vitro, no in vivo tests have been carried out at present. Herein, we described a combination therapy of local delivery of Ag and systemic antibiotics treatment in vitro in an infection model of rat. Ag nanoparticle-loaded TiO2 nanotube (NT) arrays (Ag-NTs) were fabricated on titanium implants for a customized release of Ag ion. The antibacterial properties of silver combined with antibiotics vancomycin, rifampin, gentamicin, and levofloxacin, respectively, were tested in vitro by minimum inhibitory concentration (MIC) assay, disk diffusion assay, and antibiofilm formation test. Enhanced antibacterial activity of combination therapy was observed for all the chosen bacterial strains, including gram-negative Escherichia coli (ATCC 25922), gram-positive Staphylococcus aureus (ATCC 25923), and methicillin-resistant Staphylococcus aureus (MRSA; ATCC 33591 and ATCC 43300). Moreover, after a relative short (3 weeks) combinational treatment, animal experiments in vivo further proved the synergistic antibacterial effect by X-ray and histological and immunohistochemical analyses. These results demonstrated that the combination of Ag nanoparticles and antibiotics significantly enhanced the antibacterial effect both in vitro and in vivo through the synergistic effect. The strategy is promising for clinical application to reduce the usage of antibiotics and shorten the administration time of implant-associated infection.

Human papillomavirus type 11 (HPV11) is one of the main causes of condyloma acuminatum, a widespread sexually transmitted disease. During infection of its primary target cell, keratinocytes, it is likely to encounter the autophagy pathway, which is an intracellular maintenance process that is also able to target invading pathogens. It is currently unknown whether HPV11 is targeted by autophagy or whether it is able to escape autophagy-mediated killing. Here, we investigated the autophagy response during HPV11 pseudovirion (PsV) entry in human keratinocytes. Transmission electron microscopy showed that intracellular PsVs were sequestered in lumen of double-membrane autophagosomes that subsequently appeared to fuse with lysosomes, while confocal microscopy showed induction LC3 puncta, the hallmark of induced autophagy activity. Furthermore, quantitative infection assays showed that high autophagy activity resulted in reduced HPV11 PsV infectivity. Therefore, the autophagy pathway seemed to actively target invading HPV11 PsVs for destruction in the autolysosome. Western analysis on the phosphorylation state of autophagy regulators and upstream pathways indicated that autophagy was activated through interplay between Erk and Akt signaling. In conclusion, autophagy functions as a cellular protection mechanism against intracellular HPV11 and therefore therapies that stimulate autophagy may prevent recurrent condyloma acuminatum by helping eliminate latent HPV11 infections.

Global DNA hypomethylation is a most common epigenetic alteration in human neoplasia. However, accumulative evidence shows that global DNA hypomethylation impacts tumorigenesis in a tissue-specific manner, promoting tumorigenesis in some but suppressing tumorigenesis in others including colorectal cancer. The underlying mechanisms, especially how DNA hypomethylation suppresses tumorigenesis, remain largely unknown. Here, we investigate how DNA hypomethylation affects intestinal tumorigenesis by using an Uhrf1 tandem tudor domain knockin mutant mouse model (Uhrf1ki/ki) that exhibits a moderate ~10% reduction of global DNA methylation. We found that both chemical-induced colorectal carcinogenesis and Apc loss of heterozygosity (LOH)-induced intestinal tumorigenesis are substantially suppressed in the Uhrf1 mutant mice. Furthermore, unlike Dnmt1 hypomorphic mice in which DNA hypomethylation suppresses the incidence of macroscopic intestinal tumors but promotes the formation of microadenoma in ApcMin/+ background, Uhrf1ki/ki/ApcMin/+ mice have markedly reduced incidence of both microadenoma and macroadenoma. DNA hypomethylation does not appear to affect Apc LOH, activation of the Wnt or Hippo pathway, or tumor cell proliferation, but acts cooperatively with activated Wnt pathway to enhance the caspase-3 gene expression, activation, and apoptosis. Furthermore, increased caspase-3 expression correlates with DNA hypomethylation within the caspase-3 enhancer regions. Taken together, we present a new mouse model for investigating the role of and the molecular mechanisms by which DNA hypomethylation suppresses intestinal tumorigenesis. Our finding that a moderate DNA hypomethylation is sufficient to suppress intestinal tumorigenesis by promoting caspase-3 expression and apoptosis sheds new light on DNA-methylation inhibitor-based colorectal cancer therapeutics.

As TLR2 agonists, several lipopeptides had been proved to be candidate vaccine adjuvants. In our previous study, lipopeptides mimicking N-terminal structures of the bacterial lipoproteins were also able to promote antigen-specific immune response. However, the structure-activity relationship of lipopeptides as TLR2 agonists is still unclear. Here, 23 synthetic lipopeptides with the same lipid moiety but different peptide sequences were synthesized, and their TLR2 activities in vitro and mucosal adjuvant effects to OVA were evaluated. LP1-14, LP1-30, LP1-34 and LP2-2 exhibited significantly lower cytotoxicity and stronger TLR2 activity compared with Pam2CSK4, the latter being one of the most potent TLR2 agonists. LP1-34 and LP2-2 assisted OVA to induce more profound specific IgG in sera or sIgA in BALF than Pam2CSK4. Furthermore, the possibility of LP1-34, LP2-2 and Pam2CSK4 as the mucosal adjuvant for the SARS-CoV-2 recombinant RBD (rRBD) was investigated. Intranasally immunized with rRBD plus either the novel lipopeptide or Pam2CSK4 significantly increased the levels of specific serum and respiratory mucosal IgG and IgA, while rRBD alone failed to induce specific immune response due to its low immunogenicity. The novel lipopeptides, especially LP2-2, significantly increased levels of rRBD-induced SARS-CoV-2 neutralizing antibody in sera, BALF and nasal wash. Finally, Support vector machine (SVM) results suggested that charged residues in lipopeptides might be beneficial to the agonist activity, while lipophilic residues might adversely affect the agonistic activity. Figuring out the relationship between peptide sequence in the lipopeptide and its TLR2 activity may lay the foundation for the rational design of novel lipopeptide adjuvant for COVID-19 vaccine.

In recent decades, herbal medicines have played more and more important roles in the healthcare system in the world because of the good efficacy. However, with the increasing use of herbal medicines, the toxicity induced by herbal medicines has become a global issue. Therefore, it is needed to investigate the mechanism behind the efficacy and toxicity of herbal medicines. In this study, using Aconiti Lateralis Radix Praeparata (Fuzi) as an example, we adopted a systems pharmacology approach to investigate the mechanism of Fuzi in treating rheumatoid arthritis and in inducing cardiac toxicity and neurotoxicity. The results showed that Fuzi has 25 bioactive compounds that act holistically on 61 targets and 27 pathways to treat rheumatoid arthritis, and modulation of inflammation state is one of the main mechanisms of Fuzi. In addition, the toxicity of Fuzi is linked to 32 compounds that act on 187 targets and 4 pathways, and the targets and pathways can directly modulate the flow of Na+, Ca2+, and K+. We also found out that non-toxic compounds such as myristic acid can act on targets of toxic compounds and therefore may influence the toxicity. The results not only reveal the efficacy and toxicity mechanism of Fuzi, but also add new concept for understanding the toxicity of herbal medicines, i.e., the compounds that are not directly toxic may influence the toxicity as well.

The bottleneck associated with the validation of the parameters of the entropy model has limited the application of this model to modern functional imaging technologies such as the resting-state functional magnetic resonance imaging (rfMRI). In this study, an optimization algorithm that could choose the parameters of the multiscale entropy (MSE) model was developed, while the optimized effectiveness for localizing the epileptogenic hemisphere was validated through the classification rate with a supervised machine learning method. The rfMRI data of 20 mesial temporal lobe epilepsy patients with positive indicators (the indicators of epileptogenic hemisphere in clinic) in the hippocampal formation on either left or right hemisphere (equally divided into two groups) on the structural MRI were collected and preprocessed. Then, three parameters in the MSE model were statistically optimized by both receiver operating characteristic (ROC) curve and the area under the ROC curve value in the sensitivity analysis, and the intergroup significance of optimized entropy values was utilized to confirm the biomarked brain areas sensitive to the epileptogenic hemisphere. Finally, the optimized entropy values of these biomarked brain areas were regarded as the feature vectors input for a support vector machine to classify the epileptogenic hemisphere, and the classification effectiveness was cross-validated. Nine biomarked brain areas were confirmed by the optimized entropy values, including medial superior frontal gyrus and superior parietal gyrus (p < .01). The mean classification accuracy was greater than 90%. It can be concluded that combination of the optimized MSE model with the machine learning model can accurately confirm the epileptogenic hemisphere by rfMRI. With the powerful information interaction capabilities of 5G communication, the epilepsy side-fixing algorithm that requires computing power can be integrated into a cloud platform. The demand side only needs to upload patient data to the service platform to realize the preoperative assessment of epilepsy.

Langerhans cells (LCs) and plasmacytoid dendritic cells (pDCs) play an important role in the cutaneous immune response to viral infection. Verruca vulgaris (VV) is a chronic benign disease caused by human papillomavirus (HPV) infection.To investigate the possible roles of LCs, pDCs and toll-like receptor (TLR)7/9 signaling pathways in the pathogenesis of VV, we detected the expression of CD1a, CD2AP, CD123, TLR7/9, IFN regulatory factor 7 (IRF7), and interleukin-1 receptor-associated kinase 1 (IRAK1) in VV lesions.The expression of CD1a, CD2AP, CD123, TLR7/9, IRF7, and IRAK1 in 20 VV lesions was tested by immunohistochemistry. The density and number of stained cells were compared between VV lesions and the perilesional normal skin.The density and number of CD1a-, CD2AP-, CD123-, TLR9-, and IRAK1-positive cells in the papillary layer of VV lesions were significantly higher than those in the perilesional normal skin (P < .05). There were no significant differences in the density and positive rate of CD1a+ cells in the epidermis and of TLR7 and IRF7 cells in the dermis between VV lesions and the perilesional normal skin at the edge (P > .05).In VV, the number of LCs increases only in the dermis, indicating that LC's antigen-presenting function might not be inhibited. The increased number of pDCs in VV lesions suggests that HPV infection may recruit the pDCs to the virus-infected epithelium. We speculate that the TLR7/9 downstream signaling pathway is not fully activated in VV, leading to difficulty of HPV removal and the relapse of HPV-infected lesions.

Background & Aims: Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure. Methods: Hepatocyte-specific Ppara knockout mice and littermate wild-type control mice were intraperitoneally injected with acetaminophen (400 mg/kg body weight). Blood and liver samples were collected at different time points. We measured phase I and II cytochrome P450 enzymes, glutathione, reactive oxygen species, cytokines including Il6, and pSTAT3 by reverse transcriptase quantitative PCR, colorimetric, immunohistochemistry analyses and Western blotting. Results: Hepatic expression of PPARα was significantly decreased in DILI patients. Disruption of the Ppara gene in hepatocytes significantly reduced acetaminophen-induced liver injury in mice. ROS production rather than the expression levels of phase I and II cytochrome P450 enzymes was reduced in hepatocyte-specific Ppara knockout mice compared to control mice after acetaminophen administration. Mechanistically, hepatocyte-specific Ppara knockout mice had upregulated activation of the hepatoprotective pathway IL-6/STAT3 compared to wild-type mice, as evidenced by hepatic Il6 mRNA levels, hepatic protein levels of STAT3 and phosphorylated STAT3 were much higher in hepatocyte-specific Ppara knockout mice than in wild-type mice post acetaminophen injection. Conclusions: Hepatocyte-specific disruption of the Ppara gene protects against acetaminophen-induced liver injury by reducing oxidative stress and upregulating the hepatoprotective IL-6/STAT3 signaling pathway.