Background: Acetaminophen (APAP) is commonly used as an antipyretic and analgesic agent. Excessive APAP can induce liver toxicity, known as APAP-induced liver injury (ALI). The metabolism and pathogenesis of APAP have been extensively studied in recent years, and many cellular processes such as autophagy, mitochondrial oxidative stress, mitochondrial dysfunction, and liver regeneration have been identified to be involved in the pathogenesis of ALI. Caveolin-1 (CAV-1) as a scaffold protein has also been shown to be involved in the development of various diseases, especially liver disease and tumorigenesis. The role of CAV-1 in the development of liver disease and the association between them remains a challenging and uncharted territory. Summary: In this review, we briefly explore the potential therapeutic effects of CAV-1 on ALI through autophagy, oxidative stress, and lipid metabolism. Further research to better understand the mechanisms by which CAV-1 regulates liver injury will not only enhance our understanding of this important cellular process, but also help develop new therapies for human disease by targeting CAV-1 targets. Key Messages: This review briefly summarizes the potential protective mechanisms of CAV-1 against liver injury caused by APAP.

Highlights

  • Caveolin-1 (CAV-1) has been shown to regulate mitochondrial biology, lipid accumulation, autophagy, and other signaling pathways in the liver through multiple pathways.

  • CAV-1 may be effective targets for the treatment of APAP-induced liver injury.

  • Further research to better understand the regulatory mechanisms of autophagy will not only enhance our understanding of this important cellular process, but also contribute to the development of new therapies for human diseases through autophagy.

Acetaminophen (APAP) overused is the leading cause of acute liver failure, although the frequency is variable worldwide [1]. There are nearly 50,000 emergency department visits, 26,000 hospitalizations, and 450 deaths in the USA alone per year; at least 20% of these deaths occur in patients with unintentional APAP overdose [2]. In Europe, the proportion of APAP-induced liver injury (ALI) is as high as 46% of acute liver failure cases. Patients with chronic alcohol abuse and anorexia appear to be at greatly increased risk of developing ALI [3].

The mechanism of ALI has been extensively studied [4]. At the therapeutic dose of APAP, about 25% of the dose goes through “first-pass” metabolism [5]. It is mainly acidified and sulfated by glucuronide, and then excreted through the liver, and a small part is metabolized by the cytochrome P450 system to form the reaction metabolite n-acetyl-p-benzoquinone imine (NAPQI). However, when APAP is excessive, the production of NAPQI is significantly increased, which leads to the depletion of glutathione (GSH) in the liver [6]. First, it causes necrosis of the hepatocytes closest to the central vein, and then the necrotic area radiates outward. Mitochondria are known to be important early targets for the formation of NAPQI adducts [7].

NAC was introduced rapidly in the late 1970s as an antidote against APAP poisoning, which protects GSH decreased [8]. NAC is the only clinically approved antidote. Although NAC is effective, particularly when given early after the overdose, in patients with APAP overdose for more than 8 h, the efficiency of NAC treatment was significantly reduced [9, 10]. The side effects of narrow treatment window and ineffective treatment for advanced treatment or even prolonged treatment are also of concern [11]. Some other drugs, such as 4-methylpyrazole (4-MP), methylene blue, metformin, have been reported in animal studies to be effective in preventing ALI, preclinical studies have also evaluated the potential protective mechanism of 4-MP, and if the efficacy of 4-MP is confirmed in trials in patients with APAP overdose, it may be an important adjuvant therapy for NAC [12]. Therefore, more detailed studies are needed to identify relevant therapeutic targets for limiting injury and preventing ALI [13].

Autophagy is a physiological function of mammals and plays an important role in many physiological and disease processes [14]. Macroautophagy, microautophagy, and chaperone-mediated autophagy are the three main different forms of autophagy [15]. Autophagy is a tightly coordinated process [16]. Under normal growth conditions, it specifically degrades damaged or redundant organelles, aged or damaged organelles, and eventually fuses into lysosomes, leading to the misfolded protein degradation of isolation components to help maintain the stability of cells [17]. The multiple functions of autophagy exert their potential adaptability and harmful consequences [18]. It is believed that excessive use of APAP can cause mitochondrial injury and accumulation of APAP-ADs, leading to liver necrosis and liver injury [19]. Mitochondrial injury and ATP consumption are key factors for APAP-induced hepatocyte necrosis. Autophagy contributes to the clearance of damaged mitochondria and provides energy fuel for ATP production. Therefore, it can be speculated that autophagy may be an important protective mechanism against ALI [20]. Adiponectin has been shown to prevent APAP-induced hepatotoxicity by activating AMPK and ULk11-mediated autophagy [21]. Kruppel-like factor 6 is a transcription factor and tumor suppressor that has been shown to upregulate Atg7 and Beclin-1 and have a protective effect on ALI [22]. ICR mice were intraperitoneal injection of APAP, Beclin-1 and autophagy-related protein 7 expression decreased, while P62 expression increased [23]. In addition, rapamycin reduces the hepatotoxicity of APAP by removing damaged mitochondria and APAP-ADs through autophagy [24]. Although APAP-AD formation is important, the mechanism by which hepatocytes remove APAP-AD remains unclear. Experiments have recently provided compelling evidence that autophagy helps remove APAP-AD from liver cells [25]. First, APAP-AD presented a punctate peri-nuclear pattern in hepatocytes and co-localized with autophagosomal-labeled GFP-LC3 spots and lysosomal-associated membrane protein 1. Second, both the purified liver autophagosomes and autophagosomes contained APAP-AD, and the level of APAP-AD encapsulated by autophagosomes increased in the presence of autophagy inhibitor CQ. Third, pharmacological inhibition of autophagy increased serum AP-AD levels by leupeptin. Fourth, leupeptin significantly increased the level of detergent-insoluble APAP-AD. Detergent-insoluble protein aggregation is mainly scavenged by autophagy, which further supports the role of autophagy in scavenging APAP-AD. Finally, APAP-AD is associated with autophagy receptor protein P62, and P62 knockdown results in impaired APAP-AD clearance and increases APAP-induced hepatotoxicity. In summary, these findings indicate that autophagy can protect the liver from ALI by clearing APAP-AD, as shown in Table 1.

Table 1.

Autophagy protects ALI

Therapeutic drugsEffective dose, mg/kgAnimal models/APAP doseReferences
Pterostilbene (PTE) 15/30/60 ICR mice, 400 mg/kg i.p. [26
Chlorpromazine (CPZ) C57BL/6J mice, 500 mg/kg i.p. [26
Augmenter of liver regeneration  BALB/c mice, 600 mg/kg i.p. [27
Adiponectin  C57BL/6J, 500 mg/kg i.p. [28
Baicalein 50/100 350 mg/kg [29
Therapeutic drugsEffective dose, mg/kgAnimal models/APAP doseReferences
Pterostilbene (PTE) 15/30/60 ICR mice, 400 mg/kg i.p. [26
Chlorpromazine (CPZ) C57BL/6J mice, 500 mg/kg i.p. [26
Augmenter of liver regeneration  BALB/c mice, 600 mg/kg i.p. [27
Adiponectin  C57BL/6J, 500 mg/kg i.p. [28
Baicalein 50/100 350 mg/kg [29

The rate and amount of lipid synthesis and accumulation are critical to liver health and are related to an individual’s age, gender, eating habits, and health status. The composition of liver lipids in healthy individuals is almost stable [30]. Lipid metabolism includes the digestion and absorption of lipids in the small intestine, their entry into the blood circulation by the lymphatic system (through lipoprotein transport), their conversion through the liver, their storage in adipose tissue, and their use by tissues when needed. Lipids have many important functions. They are involved in various biochemical reactions and almost all metabolic pathways in the body. Therefore, alterations in lipids affect cell function and reflect the state of cells and tissues. However, drugs such as APAP can alter the normal course of lipid metabolism in the liver [31]. APAP has been shown to inhibit fatty acid β oxidation, disrupt lipid metabolism, and increase triglyceride levels in serum and liver, and this phenomenon is irreversible. These metabolic changes disrupt liver cell function as the affected liver cells begin to accumulate lipids within the cells, initiating pathways leading to steatosis – a hallmark of liver injury [32].

Research has shown that 300 mg/kg of APAP can significantly increase serum ALT and AST levels and lead to histopathological alterations in rats [33]. It has been reported that after treatment with some Chinese herbal medicines in such mouse models, the ALI caused by APAP overdose in rats was alleviated, the serum AST and ALT levels were reduced, the GSH activity was increased, and the liver injury was significantly alleviated. The mechanism of liver injury is not always determined, but it is often accompanied by mitochondrial dysfunction, which often includes structural damage to mitochondria and changes and disorders in different metabolic pathways. Similarly, ALI excision may be related to lipid metabolism and changes in intracellular signaling proteins such as JNK1, AMPK, and p53 signaling pathways, when APAP is excess, hepatic triglycerides accumulate in lipid vacuoles surrounding hepatocyte nuclei, and denaturation of microvesicular fat mixtures in some hepatocytes may lead to liver lesions. The treatment of APAP hepatotoxicity is closely related to the regulation of lipid metabolism [34].

In the damage process of ALI, mitochondrial protein is the main target of NAPQI; NAPQI induces mitochondrial oxidative stress and produces ROS; in addition, NAPQI also interferes with the complex I/II of the mitochondrial electron transport chain, causing electrons to leak from electron transport chain into oxygen, thereby forming superoxide radicals; oxidative stress is one of the key mechanisms of ALI and is considered a potential therapeutic target. Under normal circumstances, the oxidation system and antioxidant system in the body are in dynamic equilibrium. However, for various reasons, upsetting the equilibrium will produce oxidative stress, which is mainly manifested as an imbalance between ROS and antioxidants. ROS, lipid peroxidation, and mitochondrial dysfunction lead to continuous fragmentation of nuclear DNA and eventual cell death. Persistent or intense oxidative stress may increase the risk of liver cell death, leading to a range of liver diseases [35].

In a 300 mg/kg APAP-induced mouse acute drug-induced liver injury model, APAP increased lipid peroxidation, decreased levels of enzyme antioxidants, and reduced GSH in liver tissue of APAP-poisoned mice. But this oxidative stress can be treated with boldine [36]. Too much APAP in the body can cause oxidative stress, which can destroy protein structure, increase lipid peroxidation levels, and aggravate liver injury. Oxidative stress may be a potential target for the treatment of drug-induced liver injury or an aspect that must be considered in the prevention of drug-induced liver injury.

Autophagy is a main protective pathway which is activated in cells to respond to various stressors [37]. In recent years, there has been evidence that autophagy has a cytoprotective effect in various diseases [38]. Caveolin, as a scaffold protein for specific lipids, plays an important role in a variety of signaling pathways [39]. Interestingly, CAV-1 is phosphorylated at tyrosine-14 [40], and its various functions are highly regulated by phosphorylation at this site. Studies have shown that CAV-1, as an autophagy inducer, is able to interact with BECN1/VPS34 complexes through its scaffold domain to promote autophagosome formation [41]. However, there are also studies in the stress response of human breast cancer cells, lysosomal function is improved, and the level of autophagy increases when the expression of CAV-1 is inhibited [42]. CAV-1 regulates autophagy differently under different pathological conditions.

In recent years, CAV-1, which can be used as a scaffold protein for specific lipids, is closely related to lipid accumulation, mitochondrial biology, and the regulation of autophagy, and has become a new hot spot in the research of various metabolic disorders and oxidative stress-related diseases [43]. Some studies have shown that CAV-1 and lipid rafts are involved in the regulation of autophagy. For example, CAV-1 plays an important role in the stress response of human breast cancer cells by regulating lysosomal function and autophagy [44]. Moreover, CAV-1 also plays an indispensable role in AFB1-induced hepatocyte apoptosis by regulating oxidation and autophagy [45]. These studies indicate the regulatory role of CAV-1 in autophagy. CAV-1 scaffold domain peptide cavtratin can activate the phosphorylation of AKT and PTEN in cultured N9 cells. PTEN has phosphatase activity, which can negatively regulate the PI3K/Akt signal pathway [46] and attenuate the signal from PI3K/Akt/mTOR; the signal strength upstream of the conduction pathway can inhibit cell proliferation and promote cell autophagy and apoptosis [47].

Lipid metabolism disorders refer to a group of disorders characterized by disruption of lipid metabolism, such as LDL-hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, and mixed hyperlipoproteinemia [48]. Disorders of lipid metabolism are one of the main risk factors for liver disease, diabetes, and various cardiovascular diseases. Lipid metabolism disorders are caused by abnormal lipid transport, which plays a key role in lipid transport. The cave is an abundant 50–100 nm stable lipid raft region in adipocytes, vascular endothelial cells, and fibroblasts [49]. These organelles consist of a cholesterol and sphingolipid-rich environment and feature in regulating cholesterol homeostasis, which can bind to certain receptors such as GP130 [50]. Caveolin 1–3 proteins are associated with cave formation and function. CAV-1 has been reported to be closely related to lipid metabolism, which is thought to be an intracellular lipid transport factor that can transport lipids between the cytoplasm and the cell membrane through cave vesicles. Caveolae in the plasma membrane may invade and form cave vesicles containing lipids or lipoproteins. Besides vesicles-mediated lipid transport, all sorts of receptors in the cave, such as LDLR, ABCA1, and SR-B1, are able to mediate lipid efflux [51].

In normal liver tissue, the morphological feature of hepatic stellate cells is the presence of multiple cytoplasmic lipid droplets (LDs). The cave is a small spherical invagination of the plasma membrane, playing an important role in endocytosis, cell transformation, maintaining membrane lipid composition, and signal transduction [52]. CAV-1 is related to the formation of LDs in human hepatic stellate cells, mainly by lateral fissure or cave endocytosis, which transports newly synthesized cholesterol from the endoplasmic reticulum membrane to the plasma membrane vesicles, where it is transported to high-density lipoprotein in the plasma membrane. Cholesterol transport dependent on CAV-1 seems essential, and caves are mainly used for plasma membrane cholesterol exchange between high-density lipoprotein and cell membranes. Caves mediate the unique cellular mechanism of LDs and may play a key role in the progression of liver injury [53].

Oxidative stress is the process by which cells are stimulated by the internal and external environment to produce excess active substances, especially ROS and reactive nitrogen species [54]. Normally, mitochondrial oxidative metabolism can generate ROS and a variety of organic peroxides, and hypoxia will also induce an increase in NO, which in turn causes the production of a series of active substances. When oxidative stress leads to the oxidation of intracellular proteins, nucleic acids, and lipid peroxidation enhanced, it causes irreversible damage to normal cell structure and function, further leading to somatic mutation and transformation. Therefore, abnormal oxidative stress is associated with the occurrence and progression of a variety of human diseases [55].

The cave is a type of lipid raft rich in sphingomyelins and cholesterol. Studies have shown that CAV-1 can recruit a variety of signaling molecules and receptors to aggregate in the cellar, and regulate the normal physiological activities of cells through the cascade of signaling molecules [56]. It is worth noting that the active substances produced by oxidative stress often preferentially accumulate in the membrane microregion and act as a second messenger. In recent years, studies have shown that CAV-1 has a certain regulatory effect on the state of oxidative stress in cells. After reducing the expression level of CAV-1, it promotes a series of oxidative stress reactions such as aging and inflammation of various cells. In the study of CCL4 liver injury mouse model, CAV-1−/− mice had increased liver pro-inflammatory factor secretion, increased total liver ROS level, and worsened liver damage compared with wild-type mice [57]. It has been shown that reducing the level of intracellular expression of CAV-1 can enhance cellular oxidative stress levels. With a decrease in CAV-1, although the fovelets are still able to assemble on the plasma membrane, their function is severely impaired. Oxidative stress regulates CAV-1 expression, degradation, post-translational modification, and membrane transport [58]. Antioxidants play a crucial role in preventing ALI. In mice with ALI caused by APAP, CAV-1 not only scavenges reactive oxygen species, but also acts as an antioxidant, playing a crucial role in detoxifying the metabolite NAPQI of APAP [59]. CAV-1 interacts with intracellular oxidative stress levels and is expected to become a new therapeutic target for liver injury.

CAV-1 is an important structural protein in the cell membrane, which specifically binds to some signaling molecules through its scaffold domain, and plays a crucial role in lipid metabolism, cholesterol homeostasis, and regulation of autophagy [60]. Caveolin is a vital structural functional protein of fossa cell membrane. It acts as a transport carrier and signal transduction platform on the cell membrane [61]. CAV-1 is synthesized in the endoplasmic reticulum and interacts with proteins to regulate protein activity, transport, and degradation. The expression level is different in different tissues and cell lines, and its function may vary with the disease type [62]. CSD has an 82–101 amino acid sequence of CAV-1, called the CAV-1 scaffold domain, and plays an important role in realizing the biological functions of cell signal transduction and material transmembrane transport [63]. After connecting to the homologous domain of antennae, CSD can quickly enter cells and tissues [64]. In addition, CSD has been proven to work in vivo [65]. Previous study reported that CAV-1 expression was increased in fatty liver of C57BL/6 mice fed a high-fat and high-cholesterol diet for 14 weeks, and CAV-1 expression was positively correlated with liver steatosis severity [66]. CAV-1 has also been reported to protect alcoholic liver injury by inhibiting the production of reactive nitrogen species. CAV-1 inhibits NO synthesis reaction induced by iNOS activation, reduces superoxide formation, and improves mitochondrial function to protect liver cells from ethanol damage. Current studies have shown that the expression of CAV-1 was decreased in the liver of APAP-treated mice [67]. CAV-1 deficiency gradually leads to mitochondrial failure, persistent oxidative stress, and apoptosis, which contribute to the development of the disease [68]. After partial hepatectomy, the survival rate of mice was reduced and liver regeneration was impaired, suggesting that CAV-1 may play an important role in stimulating wound repair after exposure to liver toxins such as APAP, indicating the important role of CAV-1 in regulating liver function [69].

NAC remains the only clinically approved antidote. Although it may be very effective in treating ALI by increasing the level of antioxidant GSH, especially when administered early after overdose, there are also concerns about the limited efficacy for late-stage patients and even adverse reactions to long-term treatment. In recent years, there has been increasing evidence that CAV-1 plays an important role in a variety of diseases. As an important part of caveolae, CAV-1 can regulate liver lipid accumulation, lipid and glucose metabolism, mitochondrial biology, hepatocyte proliferation, oxidative stress, and autophagy. As a polypeptide, CSD can exert CAV-1 function in vivo and can be used in clinical research. There are many uncertain factors and unknown factors; this article only summarizes some possible mechanisms of CAV-1 on ALI, as shown in Figure 1. In the future, it is necessary to further study the more specific mechanism of CAV-1 treatment of ALI. It provides a theoretical basis for the development of new drugs targeting CAV-1 for liver injury.

Fig. 1.

APAP damages mitochondria, leading to liver damage. CAV-1 may ameliorate APAP-induced acute liver failure by activating autophagy, reducing lipid accumulation and regulating oxidative stress.

Fig. 1.

APAP damages mitochondria, leading to liver damage. CAV-1 may ameliorate APAP-induced acute liver failure by activating autophagy, reducing lipid accumulation and regulating oxidative stress.

Close modal

We thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment.

The authors declare no conflict of interest. All authors have seen and approved the final version of the manuscript being submitted. They warrant that the article is the authors’ original work, has not received prior publication, and is not under consideration for publication elsewhere.

This work was supported by the National Natural Science Foundation of China (Grant No. 81970516).

Wei Jiang: methodology and writing – original draft preparation. Junping Wang: investigation. Jiarong Wang: visualization. Chengmu Hu: conceptualization, project administration, and funding acquisition. Xueran Chen and Zhiyou Fang: writing guidance.

Additional Information

Zhiyou Fang and Chengmu Hu contributed equally to this work and should be considered co-corresponding authors.

1.
Sun
Z
,
Wang
Q
,
Sun
L
,
Wu
M
,
Li
S
,
Hua
H
, et al
.
Acetaminophen-induced reduction of NIMA-related kinase 7 expression exacerbates acute liver injury
.
JHEP Rep
.
2022
;
4
(
10
):
100545
.
2.
Nourjah
P
,
Ahmad
SR
,
Karwoski
C
,
Willy
M
.
Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States
.
Pharmacoepidemiol Drug Saf
.
2006
;
15
(
6
):
398
405
.
3.
Lee
WM
.
Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away
.
J Hepatol
.
2017
;
67
(
6
):
1324
31
.
4.
Chidiac
AS
,
Buckley
NA
,
Noghrehchi
F
,
Cairns
R
.
Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease
.
Expert Opin Drug Metab Toxicol
.
2023
;
19
(
5
):
297
317
.
5.
Fisher
ES
,
Curry
SC
.
Evaluation and treatment of acetaminophen toxicity
.
Adv Pharmacol
.
2019
;
85
:
263
72
.
6.
Akakpo
JY
,
Ramachandran
A
,
Duan
L
,
Schaich
MA
,
Jaeschke
MW
,
Freudenthal
BD
, et al
.
Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-jun n-terminal kinase
.
Toxicol Sci
.
2019
;
170
(
1
):
57
68
.
7.
Ramachandran
A
,
Jaeschke
H
.
A mitochondrial journey through acetaminophen hepatotoxicity
.
Food Chem Toxicol
.
2020
;
140
:
111282
.
8.
Cai
X
,
Cai
H
,
Wang
J
,
Yang
Q
,
Guan
J
,
Deng
J
, et al
.
Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options
.
J Zhejiang Univ Sci B
.
2022
;
23
(
4
):
265
85
.
9.
Yarema
M
,
Chopra
P
,
Sivilotti
MLA
,
Johnson
D
,
Nettel-Aguirre
A
,
Bailey
B
, et al
.
Anaphylactoid reactions to intravenous N-acetylcysteine during treatment for acetaminophen poisoning
.
J Med Toxicol
.
2018
;
14
(
2
):
120
7
.
10.
Smilkstein
MJ
,
Knapp
GL
,
Kulig
KW
,
Rumack
BH
.
Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)
.
N Engl J Med
.
1988
;
319
(
24
):
1557
62
.
11.
Akakpo
JY
,
Ramachandran
A
,
Curry
SC
,
Rumack
BH
,
Jaeschke
H
.
Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose
.
Arch Toxicol
.
2022
;
96
(
2
):
453
65
.
12.
Jaeschke
H
,
Akakpo
JY
,
Umbaugh
DS
,
Ramachandran
A
.
Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure
.
Toxicol Sci
.
2020
;
174
(
2
):
159
67
.
13.
Ramachandran
A
,
Jaeschke
H
.
Acetaminophen hepatotoxicity
.
Semin Liver Dis
.
2019
;
39
(
2
):
221
34
.
14.
Kuma
A
,
Komatsu
M
,
Mizushima
N
.
Autophagy-monitoring and autophagy-deficient mice
.
Autophagy
.
2017
;
13
(
10
):
1619
28
.
15.
Behera
J
,
Ison
J
,
Tyagi
A
,
Mbalaviele
G
,
Tyagi
N
.
Mechanisms of autophagy and mitophagy in skeletal development, diseases and therapeutics
.
Life Sci
.
2022
;
301
:
120595
.
16.
Lamark
T
,
Svenning
S
,
Johansen
T
.
Regulation of selective autophagy: the p62/SQSTM1 paradigm
.
Essays Biochem
.
2017
;
61
(
6
):
609
24
.
17.
Gao
W
,
Wang
X
,
Zhou
Y
,
Wang
X
,
Yu
Y
.
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy
.
Signal Transduct Target Ther
.
2022
;
7
(
1
):
196
.
18.
Cai
X
,
Hua
S
,
Deng
J
,
Du
Z
,
Zhang
D
,
Liu
Z
, et al
.
Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury
.
ACS Appl Mater Inter
.
2022
;
14
(
38
):
42887
903
.
19.
McGill
MR
,
Lebofsky
M
,
Norris
HR
,
Slawson
MH
,
Bajt
ML
,
Xie
Y
, et al
.
Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications
.
Toxicol Appl Pharmacol
.
2013
;
269
(
3
):
240
9
.
20.
Kim
HY
,
Yoon
HS
,
Heo
AJ
,
Jung
EJ
,
Ji
CH
,
Mun
SR
, et al
.
Mitophagy and endoplasmic reticulum-phagy accelerated by a p62 ZZ ligand alleviates paracetamol-induced hepatotoxicity
.
Br J Pharmacol
.
2023
;
180
(
9
):
1247
66
.
21.
Lin
Z
,
Wu
F
,
Lin
S
,
Pan
X
,
Jin
L
,
Lu
T
, et al
.
Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice
.
J Hepatol
.
2014
;
61
(
4
):
825
31
.
22.
Sydor
S
,
Manka
P
,
Best
J
,
Jafoui
S
,
Sowa
JP
,
Zoubek
ME
, et al
.
Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury
.
Sci Rep
.
2017
;
7
(
1
):
8119
.
23.
Kang
KY
,
Shin
JK
,
Lee
SM
.
Pterostilbene protects against acetaminophen-induced liver injury by restoring impaired autophagic flux
.
Food Chem Toxicol
.
2019
;
123
:
536
45
.
24.
Ni
HM
,
McGill
MR
,
Chao
X
,
Du
K
,
Williams
JA
,
Xie
Y
, et al
.
Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice
.
J Hepatol
.
2016
;
65
(
2
):
354
62
.
25.
Chao
X
,
Wang
H
,
Jaeschke
H
,
Ding
WX
.
Role and mechanisms of autophagy in acetaminophen-induced liver injury
.
Liver Int
.
2018
;
38
(
8
):
1363
74
.
26.
Jaeschke
H
,
Akakpo
JY
,
Umbaugh
DS
,
Ramachandran
A
.
Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure
.
Toxicol Sci
.
2020
;
174
(
2
):
159
67
.
27.
Hu
T
,
Sun
H
,
Deng
WY
,
Huang
WQ
,
Liu
Q
.
Augmenter of liver regeneration protects against acetaminophen-induced acute liver injury in mice by promoting autophagy
.
Shock
.
2019
;
52
(
2
):
274
83
.
28.
Lin
Z
,
Wu
F
,
Lin
S
,
Pan
X
,
Jin
L
,
Lu
T
, et al
.
Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice
.
J Hepatol
.
2014
;
61
(
4
):
825
31
.
29.
Zhou
HC
,
Wang
H
,
Shi
K
,
Li
JM
,
Zong
Y
,
Du
R
.
Hepatoprotective effect of baicalein against acetaminophen-induced acute liver injury in mice
.
Molecules
.
2018
;
24
(
1
):
131
.
30.
Ming
YN
,
Zhang
JY
,
Wang
XL
,
Li
CM
,
Ma
SC
,
Wang
ZY
, et al
.
Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice
.
Lipids Health Dis
.
2017
;
16
(
1
):
153
.
31.
Lim
SA
,
Su
W
,
Chapman
NM
,
Chi
H
.
Lipid metabolism in T cell signaling and function
.
Nat Chem Biol
.
2022
;
18
(
5
):
470
81
.
32.
Suciu
M
,
Gruia
AT
,
Nica
DV
,
Azghadi
SMR
,
Mic
AA
,
Mic
FA
.
Acetaminophen-induced liver injury: implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway
.
Chem Biol Interact
.
2015
;
242
:
335
44
.
33.
Guo
H
,
Sun
J
,
Li
D
,
Hu
Y
,
Yu
X
,
Hua
H
, et al
.
Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation
.
Biomed Pharmacother
.
2019
;
112
:
108704
.
34.
Gungor
H
,
Ekici
M
,
Ates
MB
.
Lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on acetaminophen-induced hepatotoxicity in mice
.
Drug Chem Toxicol
.
2023
;
46
(
3
):
566
74
.
35.
Wang
M
,
Sun
J
,
Yu
T
,
Wang
M
,
Jin
L
,
Liang
S
, et al
.
Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis
.
Biomed Pharmacother
.
2022
;
149
:
112917
.
36.
Ezhilarasan
D
,
Raghunandhakumar
S
.
Boldine treatment protects acetaminophen-induced liver inflammation and acute hepatic necrosis in mice
.
J Biochem Mol Toxicol
.
2021
;
35
(
4
):
e22697
.
37.
Lamark
T
,
Johansen
T
.
Mechanisms of selective autophagy
.
Annu Rev Cell Dev Biol
.
2021
;
37
:
143
69
.
38.
Bhardwaj
M
,
Leli
NM
,
Koumenis
C
,
Amaravadi
RK
.
Regulation of autophagy by canonical and non-canonical ER stress responses
.
Semin Cancer Biol
.
2020
;
66
:
116
28
.
39.
Bi
C
,
Tham
DKL
,
Perronnet
C
,
Joshi
B
,
Nabi
IR
,
Moukhles
H
.
The oxidative stress-induced increase in the membrane expression of the water-permeable channel aquaporin-4 in astrocytes is regulated by caveolin-1 phosphorylation
.
Front Cell Neurosci
.
2017
;
11
:
412
.
40.
Lee
H
,
Volonte
D
,
Galbiati
F
,
Iyengar
P
,
Lublin
DM
,
Bregman
DB
, et al
.
Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette
.
Mol Endocrinol
.
2000
;
14
(
11
):
1750
75
.
41.
Nah
J
,
Yoo
SM
,
Jung
S
,
Jeong
EI
,
Park
M
,
Kaang
BK
, et al
.
Phosphorylated CAV1 activates autophagy through an interaction with BECN1 under oxidative stress
.
Cell Death Dis
.
2017
;
8
(
5
):
e2822
.
42.
Volonte
D
,
Vyas
AR
,
Chen
C
,
Dacic
S
,
Stabile
LP
,
Kurland
BF
, et al
.
Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence
.
J Biol Chem
.
2018
;
293
(
5
):
1794
809
.
43.
Wang
S
,
Wang
N
,
Zheng
Y
,
Zhang
J
,
Zhang
F
,
Wang
Z
.
Caveolin-1: an oxidative stress-related target for cancer prevention
.
Oxid Med Cell Longev
.
2017
;
2017
:
7454031
.
44.
Shi
Y
,
Tan
SH
,
Ng
S
,
Zhou
J
,
Yang
ND
,
Koo
GB
, et al
.
Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy
.
Autophagy
.
2015
;
11
(
5
):
769
84
.
45.
Xu
Q
,
Shi
W
,
Lv
P
,
Meng
W
,
Mao
G
,
Gong
C
, et al
.
Critical role of caveolin-1 in aflatoxin B1-induced hepatotoxicity via the regulation of oxidation and autophagy
.
Cell Death Dis
.
2020
;
11
(
1
):
6
.
46.
Volonte
D
,
Vyas
AR
,
Chen
C
,
Dacic
S
,
Stabile
LP
,
Kurland
BF
, et al
.
Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence
.
J Biol Chem
.
2018
;
293
(
5
):
1794
809
.
47.
Jia
S
,
Li
B
,
Huang
J
,
Verkhratsky
A
,
Peng
L
.
Regulation of glycogen content in astrocytes via cav-1/PTEN/AKT/GSK-3β pathway by three anti-bipolar drugs
.
Neurochem Res
.
2018
;
43
(
8
):
1692
701
.
48.
Ding
S
,
Kang
J
,
Tong
L
,
Lin
Y
,
Liao
L
,
Gao
B
.
Erchen decoction ameliorates lipid metabolism by the regulation of the protein CAV-1 and the receptors VLDLR, LDLR, ABCA1, and SRB1 in a high-fat diet rat model
.
Evid Based Complement Alternat Med
.
2018
;
2018
:
5309490
.
49.
Williams
JJ
,
Palmer
TM
.
Cavin-1: caveolae-dependent signalling and cardiovascular disease
.
Biochem Soc Trans
.
2014
;
42
(
2
):
284
8
.
50.
Pilch
PF
,
Liu
L
.
Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes
.
Trends Endocrinol Metab
.
2011
;
22
(
8
):
318
24
.
51.
Fridolfsson
HN
,
Roth
DM
,
Insel
PA
,
Patel
HH
.
Regulation of intracellular signaling and function by caveolin
.
FASEB J
.
2014
;
28
(
9
):
3823
31
.
52.
Ilha
M
,
Meira Martins
LA
,
da Silveira Moraes
K
,
Dias
CK
,
Thomé
MP
,
Petry
F
, et al
.
Caveolin-1 influences mitochondrial plasticity and function in hepatic stellate cell activation
.
Cell Biol Int
.
2022
;
46
(
11
):
1787
800
.
53.
Yokomori
H
,
Ando
W
,
Oda
M
.
Caveolin-1 is related to lipid droplet formation in hepatic stellate cells in human liver
.
Acta Histochem
.
2019
;
121
(
2
):
113
8
.
54.
Costa
LG
,
Garrick
JM
,
Roquè
PJ
,
Pellacani
C
.
Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more
.
Oxid Med Cell Longev
.
2016
;
2016
:
2986796
.
55.
Forman
HJ
,
Zhang
H
.
Targeting oxidative stress in disease: promise and limitations of antioxidant therapy
.
Nat Rev Drug Discov
.
2021
;
20
(
9
):
689
709
.
56.
Guan
X
,
Wang
N
,
Cui
F
,
Liu
Y
,
Liu
P
,
Zhao
J
, et al
.
Caveolin-1 is essential in the differentiation of human adipose-derived stem cells into hepatocyte-like cells via an MAPK pathway-dependent mechanism
.
Mol Med Rep
.
2016
;
13
(
2
):
1487
94
.
57.
Ji
DG
,
Zhang
Y
,
Yao
SM
,
Zhai
XJ
,
Zhang
LR
,
Zhang
YZ
, et al
.
Cav-1 deficiency promotes liver fibrosis in carbon tetrachloride (CCl4)-induced mice by regulation of oxidative stress and inflammation responses
.
Biomed Pharmacother
.
2018
;
102
:
26
33
.
58.
Wang
S
,
Wang
N
,
Zheng
Y
,
Zhang
J
,
Zhang
F
,
Wang
Z
.
Caveolin-1: an oxidative stress-related target for cancer prevention
.
Oxid Med Cell Longev
.
2017
;
2017
:
7454031
.
59.
Gardner
CR
,
Gray
JP
,
Joseph
LB
,
Cervelli
J
,
Bremer
N
,
Kim
Y
, et al
.
Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity
.
Toxicol Appl Pharmacol
.
2010
;
245
(
1
):
36
46
.
60.
Zhao
Y
,
Jia
X
,
Yang
X
,
Bai
X
,
Lu
Y
,
Zhu
L
, et al
.
Deacetylation of Caveolin-1 by Sirt6 induces autophagy and retards high glucose-stimulated LDL transcytosis and atherosclerosis formation
.
Metabolism
.
2022
;
131
:
155162
.
61.
Tsai
TH
,
Tam
K
,
Chen
SF
,
Liou
JY
,
Tsai
YC
,
Lee
YM
, et al
.
Deletion of caveolin-1 attenuates LPS/GalN-induced acute liver injury in mice
.
J Cell Mol Med
.
2018
;
22
(
11
):
5573
82
.
62.
Fu
P
,
Chen
F
,
Pan
Q
,
Zhao
X
,
Zhao
C
,
Cho
WCS
, et al
.
The different functions and clinical significances of caveolin-1 in human adenocarcinoma and squamous cell carcinoma
.
Onco Targets Ther
.
2017
;
10
:
819
35
.
63.
Hoop
CL
,
Sivanandam
VN
,
Kodali
R
,
Srnec
MN
,
van der Wel
PCA
.
Structural characterization of the caveolin scaffolding domain in association with cholesterol-rich membranes
.
Biochemistry
.
2012
;
51
(
1
):
90
9
.
64.
Gopu
V
,
Fan
L
,
Shetty
RS
,
Nagaraja
MR
,
Shetty
S
.
Caveolin-1 scaffolding domain peptide regulates glucose metabolism in lung fibrosis
.
JCI Insight
.
2020
;
5
(
19
):
e137969
.
65.
Gao
L
,
Zhou
Y
,
Zhong
W
,
Zhao
X
,
Chen
C
,
Chen
X
, et al
.
Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species
.
Hepatology
.
2014
;
60
(
2
):
687
99
.
66.
Qiu
Y
,
Liu
S
,
Chen
HT
,
Yu
CH
,
Teng
XD
,
Yao
HT
, et al
.
Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease
.
Hepatobiliary Pancreat Dis Int
.
2013
;
12
(
6
):
630
6
.
67.
Jiang
Y
,
Krantz
S
,
Qin
X
,
Li
S
,
Gunasekara
H
,
Kim
YM
, et al
.
Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy
.
Redox Biol
.
2022
;
52
:
102304
.
68.
Zhang
L
,
Xu
J
,
Liu
R
,
Chen
W
,
Chen
Q
,
Hu
W
, et al
.
Caveolin-1 protects retinal ganglion cells against acute ocular hypertension injury via modulating microglial phenotypes and distribution and activating AKT pathway
.
Sci Rep
.
2017
;
7
(
1
):
10716
.
69.
Guan
X
,
Wang
N
,
Cui
F
,
Liu
Y
,
Liu
P
,
Zhao
J
, et al
.
Caveolin-1 is essential in the differentiation of human adipose-derived stem cells into hepatocyte-like cells via an MAPK pathway-dependent mechanism
.
Mol Med Rep
.
2016
;
13
(
2
):
1487
94
.