TREM2 protects against inflammation by regulating the release of mito-DAMPs from hepatocytes during liver fibrosis.

BACKGROUND: Liver fibrosis typically develops as a result of chronic liver injury, which involves inflammatory and regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressing in hepatic non-parenchymal cells, plays a crucial role in regulating the function of macrophages. However, its mechanism in liver fibrosis remains poorly defined. METHODS: Experimental liver fibrosis models in wild type and TREM2-/- mice, and in vitro studies with AML-12 cells and Raw264.7 cells were conducted. The expression of TREM2 and related molecular mechanism were evaluated by using samples from patients with liver fibrosis. RESULTS: We demonstrated that TREM2 was upregulated in murine model with liver fibrosis. Mice lacking TREM2 exhibited reduced phagocytosis activity in macrophages following carbon tetrachloride (CCl4) intoxication. As a result, there was an increased accumulation of necrotic apoptotic hepatocytes. Additionally, TREM2 knockout aggravated the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from dead hepatocytes during CCl4 exposure, and further promoted the occurrence of macrophage-mediated M1 polarization. Then, TREM2-/- mice showed more serious fibrosis pathological changes. In vitro, the necrotic apoptosis inhibitor GSK872 effectively alleviated the release of mito-DAMPs in AML-12 cells after CCl4 intoxication, which confirmed that mito-DAMPs originated from dead liver cells. Moreover, direct stimulation of Raw264.7 cells by mito-DAMPs from liver tissue can induce intracellular inflammatory response. More importantly, TREM2 was elevated and inflammatory factors were markedly accumulated surrounding dead cells in the livers of human patients with liver fibrosis. CONCLUSION: Our study highlights that TREM2 serves as a negative regulator of liver fibrosis, suggesting its potential as a novel therapeutic target.

Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.

The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.

Aberrant mitochondrial aggregation of TDP-43 activated mitochondrial unfolded protein response and contributed to recovery of acetaminophen induced acute liver injury.

Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.

High-fat diet exacerbated motor dysfunction via necroptosis and neuroinflammation in acrylamide-induced neurotoxicity in mice.

Health risks associated with acrylamide (ACR) or high-fat diet (HFD) exposure alone have been widely concerned in recent years. In a realistic situation, ACR and HFD are generally co-existence, and both are risk factors for the development of neurological diseases. The purpose of the present study was to investigate the combined effects of ACR and HFD on the motor nerve function. As a result, neurobehavioral tests and Nissl staining disclosed that long-term HFD exacerbated motor dysfunction and the damage of spinal cord motor neurons in ACR-exposed mice. Co-exposure of ACR and HFD resulted in morphological changes in neuronal mitochondria of the spinal cord, a significantly reduced mitochondrial subunits NDUFS1, UQCRC2, and MTCO1, released the mitochondrial DNA (mtDNA) into the cytoplasm, and promoted the production of reactive oxygen species (ROS). Combined exposure of HFD and ACR activated the calpain/CDK5/Drp1 axis and caused the mitochondrial excessive division, ultimately increasing MLKL-mediated necroptosis in spinal cord motor neurons. Meanwhile, HFD significantly exacerbated ACR-induced activation of NFkB, NLRP3 inflammasome, and cGAS-STING pathway. Taken together, our findings demonstrated that combined exposure of ACR and HFD aggravated the damage of spinal cord motor neurons via neuroinflammation and necroptosis signaling pathway, pointing to additive effects in mice than the individual stress effects.

Chronic carbon disulfide exposure induces parkinsonian pathology via α-synuclein aggregation and necrosome complex interaction.

Exposure to carbon disulfide (CS2) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS2 exposure on parkinsonian pathology. Our results showed that CS2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, in vitro and in vivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS2 exposure. Taken together, our results demonstrate that CS2-mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.

Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.

Carbon tetrachloride (CCl4)-mediated liver damage has been well recognized, but the sources and mechanisms of mitochondrial damage during this progress still remain poorly understood. Accumulating evidence has revealed that LonP1-TDP-43 pathway affect proper mitochondrial integrity and function in neurodegenerative diseases. The current study aims to investigate whether mitochondrial oxidative stress regulate LonP1-TDP-43 pathway and the possible roles of this pathway in CCl4-driven liver fibrosis. We found that TDP-43 interacted with LonP1 in chronic CCl4 exposure-induced hepatic fibrogenesis. Moreover, CCl4 led to deficiency of LonP1 and excessive accumulation of TDP-43 on mitochondria. Particularly, the gene correlation analysis for liver fibrosis patients RNA sequencing (RNA-seq) results (GSE159676) showed an obvious negative correlation between LonP1 and TDP-43. By contrast, MitoQ enhanced the occurrence of mitochondrial unfolded protein response (mtUPR), especially the activation of LonP1 after CCl4 treatment. Importantly, mitochondrial antioxidant also promoted the degradation of TDP-43 and alleviated mitochondrial damage. In addition, our results showed that CCl4 induced the release of mitochondrial DNA (mtDNA) and effectively elevated cGAS-STING-mediated immune response, which can be inhibited by MitoQ. Finally, MitoQ prevented CCl4-induced liver fibrosis. Together, our study revealed that LonP1-TDP-43 pathway mediated by mitochondrial oxidative stress participated in the progress of CCl4-drived liver fibrosis. Therefore, mitigating or reversing mitochondrial damage through targeting LonP1-TDP-43 pathway may serve as a promising therapeutic strategy for CCl4 exposure-induced liver diseases.

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide-induced dying-back neuropathy.

Acrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, non-canonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission. What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like protein (MLKL), aggregated in mitochondrial fractions. Rapamycin intervention removed the impaired mitochondria, inhibited necroptosis for axon maintenance and neuronal survival, and alleviated ACR neuropathy. Our work clarified the functional links among mitophagy, necroptosis, and SARM1-dependent axonal destruction during ACR intoxication, providing novel therapeutic targets for dying-back neuropathies.

Increased IP3R-3 degradation induced by acrylamide promoted Ca2+-dependent calpain activation and axon damage in rats.

Occupational and environmental exposure to acrylamide (ACR) can cause selective peripheral and central nerve fiber degeneration. IP3R-3 is an important transmembrane Ca2+ channel on the endoplasmic reticulum (ER), previous studies have found that ACR could induce Ca2+-dependent calpain activation and axon injury, but the exact role of IP3R-3 in ACR neuropathy is still unclear. Here we show that ACR exposure (40 mg/kg) markedly increased the ubiquitination of IP3R-3 in rat spinal cords, and promoted the degradation of IP3R-3 through the ubiquitin-proteasome pathway. Furthermore, the normal structure of ER, especially the mitochondrial associated membranes (MAMs) component, was significantly impaired in ACR neuropathy, and the ER stress pathway was activated, which indicated that the aberrant increase of cytoplasmic Ca2+ could be attributed the destruction of IP3R-3. Further investigation demonstrated that the proteasome inhibitor MG-132 effectively rescued the IP3R-3 loss, attenuated the intracellular Ca2+ increase, and reduced the axon loss of Neuron 2a (N2a) cells following ACR exposure. Moreover, the calpain inhibitor ALLN also reduced the loss of IP3R-3 and axon injury in N2a cells, but did not alleviate the Ca2+ increase in cytosol, supporting that the abnormal ubiquitination of IP3R-3 was the upstream of the cellular Ca2+ rise and axon damage in ACR neuropathy. Taken together, our results suggested that the aberrant IP3R-3 degradation played an important role in the disturbance of Ca2+ homeostasis and the downstream axon loss in ACR neuropathy, thus providing a potential therapeutic target for ACR neurotoxicity.

Mitochondrial dysfunction promotes the necroptosis of Purkinje cells in the cerebellum of acrylamide-exposed rats.

Acrylamide (ACR) is a common neurotoxicant that can induce central-peripheral neuropathy in human beings. ACR from occupational setting and foods poses a potential threat to people's health. Purkinje cells are the only efferent source of cerebellum, and their output is responsible for coordinating motor activity. Recent studies have reported that Purkinje cell injury is one of the earliest neurotoxicity at any dose rate of ACR. However, the mechanism underlying ACR-mediated damage to Purkinje cells remains unclear. This research aimed to investigate whether necroptosis is involved in ACR-induced Purkinje cell death and its regulatory mechanism. In this study, rats were treated with ACR (40 mg/kg/every other day) for 6 weeks to establish an animal model of ACR neuropathy. Furthermore, an intervention experiment was achieved by rapamycin (RAPA), which is commonly used to activate mitophagy and maintain mitochondrial homeostasis. The results demonstrated ACR exposure caused necroptosis of Purkinje cells, mitochondrial dysfunction, and inflammatory response. By contrast, RAPA alleviated mitochondrial dysfunction and inhibited activation of necroptosis signaling pathway following ACR. In conclusion, our findings suggest that mitochondrial dysfunction and activation of necroptotic signaling are associated with the loss of Purkinje cells in ACR poisoning, which can be a potential therapeutic target for ACR neurotoxicity.

The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy.

Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile-α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up-regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non-competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 µM BBE against ACR-induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR-intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR-poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1-dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1-dependent axonal destruction pathway.

MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK/YAP pathway.

Background: Liver fibrosis is a pathological wound-healing response caused by chronic liver damage. Mitochondria regulate hepatic energy metabolism and oxidative stress. Accumulating evidence has revealed that increased mitochondrial oxidative stress contributes to the activation of fibrogenesis. However, the roles and underlying mechanisms of mitochondrial oxidative stress in liver fibrosis remain unknown. Methods and results: In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, intervention experiments were achieved by CCl4 combined with the intraperitoneal injection of mitoquinone mesylate (mitoQ). We demonstrated that the chronic CCl4 exposure resulted in severe hepatic fibrogenesis and significantly promoted the production of reactive oxygen species (ROS) and mitochondrial abnormalities. Besides, JNK/YAP pathway was also activated. By contrast, the administration of mitoQ markedly inhibited the expression of pro-fibrogenic transforming growth factor-ß as well as type I collagen. The antifibrotic effects of mitoQ were also confirmed by hematoxylin and eosin staining and Sirius red staining. Moreover, mitoQ substantially reduced CCl4-induced mitochondrial damage and the release of ROS. Further studies suggested that this protection against liver fibrosis was mechanistically related to the inhibition of phosphorylation of JNK and the nuclear translocation of YAP. Conclusion: In conclusion, these findings revealed that mitoQ attenuated liver fibrosis by inhibiting ROS production and the JNK/YAP signaling pathway. Selective targeting JNK/YAP may serve as a therapeutic strategy for retarding progression of chronic liver disease.

Drp1-mediated mitochondrial fission promotes carbon tetrachloride-induced hepatic fibrogenesis in mice.

Background: Mitochondrial dynamics is essential for the maintenance of healthy mitochondrial network. Emerging evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of hepatic fibrogenesis following chronic liver injury. However, the role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in the context of liver fibrosis remains unclear. Methods and Results: In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, mitochondrial fission intervention experiments were achieved by the mitochondrial division inhibitor 1 (Mdivi-1). The results demonstrated that chronic CCl4 exposure resulted in severe hepatic fibrogenesis and mitochondrial damage. By contrast, pharmacological inhibition of mitochondrial division by Mdivi-1 substantially reduced the changes of mitochondrial dynamics and finally prevented the deposition of extracellular matrix proteins. Mechanistically, excessive mitochondrial fission may activate hepatic stellate cells through RIPK1-MLKL-dependent hepatocyte death, which ultimately promotes liver fibrosis. Conclusion: Our study imply that inhibiting Drp1-mediated mitochondrial fission attenuates CCl4-induced liver fibrosis and may serve as a therapeutic target for retarding progression of chronic liver disease.

Calpain-mediated cleavage of mitochondrial fusion/fission proteins in acetaminophen-induced mice liver injury.

Mitochondrial dysfunction was considered to be a critical event in acetaminophen (APAP) -induced hepatotoxicity. Recent studies suggest that abnormal mitochondrial dynamics contributes to mitochondrial dysfunction in APAP-induced liver injury, yet the underlying mechanisms responsible for deregulated mitochondrial dynamics remains elusive. In this study, C57BL/6 mice were used to establish a model of acute liver injury via intraperitoneal (i.p.) injection with overdose of APAP. Furthermore, calpain intervention experiments were achieved by the inhibitors ALLN or calpeptin. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in mitochondrial dynamics and calpain degradative pathway were determined by electron microscopy, immunoblot and calpain activity kit. The results demonstrated that APAP overdose resulted in a severe liver injury, mitochondrial damage and an obvious cleavage of fusion/fission proteins. Meanwhile, the activation of calpain degradative machinery in liver were observed following APAP. By contrast, pretreatment of calpain inhibitors significantly inhibited the activation of calpains. Our further investigation found that ALLN or calpeptin administration significantly suppresses the changes of mitochondrial dynamics in APAP-treated mice and finally protected against APAP-induced hepatoxicity. Overall, these results suggest that calpain-mediated cleavage of mitochondrial dynamics proteins was involved in the pathogenic process of mitochondrial dysfunction and thus present a potential molecular coupling APAP-induced hepatotoxicity.

Activation of mitophagy by rapamycin eliminated the accumulation of TDP-43 on mitochondrial and promoted the resolution of carbon tetrachloride-induced liver fibrosis in mice.

Liver fibrosis can lead to liver cirrhosis and hepatocellular carcinoma, and no effective treatment is available in clinical practice. Mitochondrial dysfunction is thought to be closely related to the development of liver fibrosis. Recent studies have reported that abnormal accumulation of TDP-43 on mitochondria may interfere with mitochondrial function in neurodegenerative disorders. However, whether aberrant TDP-43 aggregation is also involved in liver fibrosis has not been investigated. In this study, C57/BL6 mice were treated with CCl4 (escalating doses, three times a week) for 8 weeks to establish a model of liver fibrosis. Furthermore, mitophagy intervention experiment was achieved by the activator rapamycin (RAPA). The results demonstrated that chronic CCl4 exposure resulted in severe mitochondrial damage, inflammatory response and hepatic fibrogenesis. Interestingly, abnormal aggregation of TDP-43 on mitochondria was observed. By contrast, RAPA administration could promote the regression of liver fibrosis. Mechanistically, RAPA could eliminate the accumulation of TDP-43 on mitochondrial through enhancing mitophagy, thereby improving mitochondrial function. Taken together, our study revealed that mitochondrial damage induced by abnormal accumulation of TDP-43 has been implicated in the progression of liver fibrosis. Targeted clearance of mitochondrial TDP-43 may lead to the development of some anti-fibrotic therapies.

Atg7 Knockout Alleviated the Axonal Injury of Neuro-2a Cells Induced by Tri-Ortho-Cresyl Phosphate.

Autophagy is believed to be essential for the maintenance of axonal homeostasis in neurons. However, whether autophagy is causally related to the axon degeneration in organophosphorus-induced delayed neuropathy (OPIDN) still remains unclear. This research was designed to investigate the role of autophagy in axon degeneration following tri-ortho-cresyl phosphate (TOCP) in an in vitro model. Differentiated wild-type and Atg7-/- neuro-2a (N2a) cells were treated with TOCP for 24 h. Axonal degeneration in N2a cells was quantitatively analyzed; the key molecules responsible for axon degeneration and its upstream signaling pathway were determined by Western blotting and real-time PCR. The results found that Atg7-/- cells exhibited a higher resistance to TOCP insult than wild-type cells. Further study revealed that TOCP caused a significant decrease in pro-survival factors NMNATs and SCG10 and a significant increase in pro-degenerative factor SARM1 in both cells. Notably, Atg7-/- cells presented a higher level of pro-survival factors and a lower level of pro-degenerative factors than wild-type cells in the same setting of TOCP administration. Moreover, DLK-MAPK pathway was activated following TOCP. Altogether, our results suggest that autophagy is able to affect TOCP-induced axonal injury via regulating the balance between pro-survival and pro-degenerative factors, providing a promising avenue for the potential therapy for OPIDN patients.

Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation.

Mitochondrial dysfunction was considered as a critical event involved in acetaminophen (APAP)-induced acute liver injury. Mitophagy is a type of autophagy responsible for the selective removal of damaged mitochondria. However, the exact role and possible mechanism of mitophagy in APAP-induced hepatotoxicity remains largely unknown. In this study, C57/BL6 mice were used to establish a model of acute liver injury via intraperitoneal (i.p.) injection with different doses of APAP. Furthermore, autophagy intervention experiments were achieved by the administration of rapamycin (RAPA) or chloroquine (CQ) one hour prior to dosing 300 mg/kg APAP. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in mitophagy and NLRP3 inflammasome pathway were determined by electron microscopy, immunoblot, immunofluorescence and real-time PCR. The results demonstrated that APAP overdose resulted in an activation of PINK1/Parkin-mediated mitophagy in mice liver. Moreover, the expression of the critical molecules in NF-kB and NLRP3 inflammasome signaling pathway were markedly increased by APAP. Our further investigation found that pretreatment with RAPA protected against APAP-induced hepatoxicity in mice. Notably, RAPA significantly inhibited the activation of NF-kB and NLRP3 inflammasome and the production of IL-1ß in APAP-treated mice. By contrast, pretreatment with CQ further enhanced NLRP3 inflammasome signaling pathway. Taken together, these results indicated that activation of PINK1/Parkin-mediated mitophagy protects against APAP-induced acute liver injury in mice through inhibiting inflammasome activation. Therefore, mitophagy may represent a promising therapeutic target for APAP-induced liver injury.

Autophagy and acetaminophen-induced hepatotoxicity.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. APAP overdose can induce acute liver injury in humans, which is responsible for approximately 50% of total cases of acute liver failure in the United States and some European countries. Currently, the metabolism of APAP in the body has been extensively investigated; however, the exact mechanisms for APAP hepatotoxicity are not well understood. Recent studies have shown that mitochondrial dysfunction, oxidative stress and inflammatory responses play a critical role in the pathogenesis of APAP hepatotoxicity. Autophagy is a catabolic machinery aimed at recycling cellular components and damaged organelles in response to a variety of stimuli, such as nutrient deprivation and toxic stress. Increasing evidence supports that autophagy is involved in the pathophysiological process of APAP-induced liver injury. In this review, we summarized the changes of autophagy in the liver following APAP intoxication and discussed the role and its possible mechanisms of autophagy in APAP hepatotoxicity. Furthermore, this review highlights the crosstalk between mitophagy, oxidative stress and inflammation in APAP-induced liver injury and presents some possible molecular mechanisms by which activated autophagy protects against APAP-induced liver injury.