Male C57BL/6 mice were from the Experimental Animal Center of Xian Jiaotong University. The animal experiment procedures were performed in accordance with the Guide of Laboratory Animal Care and Use from the United States National Institution of Health and were approved by the Laboratory Animal Care Committee (LACC) of Xian Jiaotong University, China (No. XJTULAC2017-207). Mice were initially housed for 7 days to adjust to the environment. The experimental design included five groups (n = 10 per group): the control group included the saline control (0.9% saline) group, and the test groups included APAP, APAP + UTI (5 x 10⁴ units/kg and 1 x 10⁵ units/kg), APAP + Fer-1 (10 mg/kg), and APAP + Res (50 mg/kg) treatments administered by tail vein or intraperitoneal injection.

C57BL/6 mice at 6-8 weeks were intraperitoneally injected with D-GalN/LPS (1772-03-8/L2880, Sigma-Aldrich, USA) at a dose of 700 mg/kg and 10 ug/kg, respectively. The constructed D-GaIN/LPS-induced ALI model mice were named the model group, and the normal mice injected with phosphate-buffered saline (PBS) were named the blank group. After 1 h of LPS/D-GalN treatment, Exo and Ba-Exo (150 ug/mice) were injected into the tail vein of the mice in the Exo and Ba-Exo groups, respectively. Mice were sacrificed via anesthesia overdose 12 h after the intervention. Half of the liver tissue was fixed in paraformaldehyde, while the other half was frozen at 80 . Peripheral blood serum was stored at -80 .

C57BL/6 mice at 6-8 weeks were intraperitoneally injected with D-GalN/LPS (1772-03-8/L2880, Sigma-Aldrich, USA) at a dose of 700 mg/kg and 10 ug/kg, respectively. The constructed D-GaIN/LPS-induced ALI model mice were named the model group, and the normal mice injected with phosphate-buffered saline (PBS) were named the blank group. After 1 h of LPS/D-GalN treatment, Exo and Ba-Exo (150 ug/mice) were injected into the tail vein of the mice in the Exo and Ba-Exo groups, respectively. Mice were sacrificed via anesthesia overdose 12 h after the intervention. Half of the liver tissue was fixed in paraformaldehyde, while the other half was frozen at 80 . Peripheral blood serum was stored at -80 .

Male C57BL/6 mice aged 8-10 weeks were purchased from Guangdong Experimental Animal Center (Guangzhou, China). The animals were maintained on a 12 h light-dark cycle in a regulated temperature and humidity environment for 1 week before drug administration. (+)-CLA (50 mg/kg/day, i.g.) or fer-1 (2.5 umol/kg/day, i.p.)were administered for 7 consecutive days. To induce liver injury, mice were injected with erastin (100 mg/kg/day, i.p., twice a day) on both the 6th and 7th day, or a single dose of APAP (600 mg/kg/day, i.p.) on the 7th day after overnight food deprivation. The serum and livers were obtained for analysis.

C57BL/6 mice (Male, 6-8 weeks old, 20 g± 2 g) were purchased from Chengdu Yaokang Biotechnology Co., Ltd. (Chengdu, China). All animals were housed in the animal room of Shaanxi University ofTraditional Chinese Medicine, at a temperature of 22 ± 2 and a humidity of 40% ± 5%, alternating between light and dark. In the study, the mice were randomly divided into six groups (n = 10 in each group): the blank group, model group,XJZ high dose group, XJZ medium dose group, XJZ low dose group, and positive control (omeprazole) group. The mice in the model group were given Aspirin (300 mg/kg) via gavage for 14 days; the mice in the XJZ high dose group, XJZ medium dose group, and XJZ low dose group were given aspirin (300 mg/kg) by gavage in the morning and three different concentrations (12 g/kg, 6 g/kg, or 3 g/kg) of XJZ decoction by gavage in the afternoon; the mice in the positive control group were given aspirin (300 mg/kg) by gavage in the morning andomeprazole(20 mg/kg) by gavage in the afternoon. After the model was successfully constructed, the mice were anesthetized with isoflurane and gastric tissues were extracted for analysis.

Male C57BL/6 mice were from the Experimental Animal Center of Xian Jiaotong University. The animal experiment procedures were performed in accordance with the Guide of Laboratory Animal Care and Use from the United States National Institution of Health and were approved by the Laboratory Animal Care Committee (LACC) of Xian Jiaotong University, China (No. XJTULAC2017-207). Mice were initially housed for 7 days to adjust to the environment. The experimental design included five groups (n = 10 per group): the control group included the saline control (0.9% saline) group, and the test groups included APAP, APAP + UTI (5 x 10⁴ units/kg and 1 x 10⁵ units/kg), APAP + Fer-1 (10 mg/kg), and APAP + Res (50 mg/kg) treatments administered by tail vein or intraperitoneal injection.

APAP-induced liver injury model was induced byintraperitoneal injection 300 mg/kg APAP. The mice of APAP + abietic acid (10, 20, 40 mg/kg) were given abietic acid by intraperitoneal injection 1 h before APAP treatment. The doses of abietic acid used in this study were based on previous studies. Twelve hours later, the mice were sacrificed after anesthesia with 1%pentobarbital (50 mg/kg) injected intraperitoneally and the samples were collected.

Male BALB/c mice (8-week-old, 20-22 g) were purchased from Guangdong Medical Laboratory Animal Center (Guangzhou, China). The experimental animals were fed adaptively for one week in the Experimental Animal Center of Guangdong Pharmaceutical University (Guangzhou, China). Feeding conditions were set at 26 , humidity 65% and a lightdark cycle for 12 hours. All animal experiments were performed following the Guide for the Care and Use of Laboratory Animals, and the procedures were approved by the Research Ethical Committee of Guangdong Pharmaceutical University (gdpulacspf2020007).

Mice were randomly divided into four groups as follows (n = 5): (1) control, (2) APAP (MCE, Monmouth Junction, NJ, USA), (3) olive oil + APAP (oil + APAP), and (4) ASX (Energy Chemical, Shanghai, China) dissolved in olive oil + APAP (ASX + APAP). Astaxanthin was dissolved in olive oil to obtain a mixture of 20 mg/mL. Mice in groups 3 and 4 were given a dose of olive oil and a mixture of 5 mL/kgBW by gavage every day for 2 weeks. On day 15, mice in groups 2, 3, and 4 were given a peritoneal injection of 500 mg/kg APAP to induce liver injury. The mice were fasted for 12 h before the administration of APAP. Ten hours after APAP administration, blood and liver tissue were collected for further examination and analyses. Blood was centrifuged to obtain supernatants,which were stored at -80. Liver tissues were immediately removed from each animal, and homogenates were processed with formaldehyde and glutaraldehyde for protein and histological analysis.

The mice were treated with intraperitoneal administration (i.p.) of oil (control group) or a mixture of CCl4 (50%) and oil (50%) at a dosage of 2 ml/kg body weight. In the bicyclol-treated group, mice accepted administration of 200 mg/kg (using 0.5% carboxymethyl cellulose as solvent) by gavage three times a day 1 h before CCl4 exposure, while other groups accepted vehicles of the equal volume. Fer-1 was prepared in DMSO (5 mg/kg), andi.p. injected into mice once 1 h before CCl4 exposure. The dosage of bicyclol was consistent with our previous work. The mice were then sacrificed to collect liver and serum samples after 24 or 48 h.

All mice were randomly divided into a 2 x 2 factorial arrangement, fed diets containing 40 mg/kg or 5000 mg/kg FeSO4 (the basis of the diet was AIN-93), and gavaged with PBS or 50 mg EGCG/kg body weight per day, respectively. The experiment lasted for 6 weeks, including a 1-week adaptation and a 3-week EGCG gavage; then, all mice were euthanized.

8-week-old Nrf2-knockout (Nrf2-/-) and wild-type (WT) littermate male mice on a C57BL/6J background (provided by the RIKEN Bio-Resource Center through the National Bio-Resource Project of MEXT, Japan) were used for in vivo experiments. Intestinal ischemia was induced by clamping of the superior mesenteric artery after the intraperitoneal injection of 50 mg/kg of sodium pentobarbital. After 90 min, the intestine was reperfused for the times indicated. Sham control mice underwent the same procedure without vascular occlusion.

Male C57BL/6 mice were from the Experimental Animal Center of Xian Jiaotong University. The animal experiment procedures were performed in accordance with the Guide of Laboratory Animal Care and Use from the United States National Institution of Health and were approved by the Laboratory Animal Care Committee (LACC) of Xian Jiaotong University, China (No. XJTULAC2017-207). Mice were initially housed for 7 days to adjust to the environment. The experimental design included five groups (n = 10 per group): the control group included the saline control (0.9% saline) group, and the test groups included APAP, APAP + UTI (5 x 10⁴ units/kg and 1 x 10⁵ units/kg), APAP + Fer-1 (10 mg/kg), and APAP + Res (50 mg/kg) treatments administered by tail vein or intraperitoneal injection.

Male C57BL/6 mice were from the Experimental Animal Center of Xian Jiaotong University. The animal experiment procedures were performed in accordance with the Guide of Laboratory Animal Care and Use from the United States National Institution of Health and were approved by the Laboratory Animal Care Committee (LACC) of Xian Jiaotong University, China (No. XJTULAC2017-207). Mice were initially housed for 7 days to adjust to the environment. The experimental design included five groups (n = 10 per group): the control group included the saline control (0.9% saline) group, and the test groups included APAP, APAP + UTI (5 x 10⁴ units/kg and 1 x 10⁵ units/kg), APAP + Fer-1 (10 mg/kg), and APAP + Res (50 mg/kg) treatments administered by tail vein or intraperitoneal injection.

APAP-induced liver injury model was induced byintraperitoneal injection 300 mg/kg APAP. The mice of APAP + abietic acid (10, 20, 40 mg/kg) were given abietic acid by intraperitoneal injection 1 h before APAP treatment. The doses of abietic acid used in this study were based on previous studies. Twelve hours later, the mice were sacrificed after anesthesia with 1%pentobarbital (50 mg/kg) injected intraperitoneally and the samples were collected.

Mice were randomly divided into four groups as follows (n = 5): (1) control, (2) APAP (MCE, Monmouth Junction, NJ, USA), (3) olive oil + APAP (oil + APAP), and (4) ASX (Energy Chemical, Shanghai, China) dissolved in olive oil + APAP (ASX + APAP). Astaxanthin was dissolved in olive oil to obtain a mixture of 20 mg/mL. Mice in groups 3 and 4 were given a dose of olive oil and a mixture of 5 mL/kgBW by gavage every day for 2 weeks. On day 15, mice in groups 2, 3, and 4 were given a peritoneal injection of 500 mg/kg APAP to induce liver injury. The mice were fasted for 12 h before the administration of APAP. Ten hours after APAP administration, blood and liver tissue were collected for further examination and analyses. Blood was centrifuged to obtain supernatants,which were stored at -80. Liver tissues were immediately removed from each animal, and homogenates were processed with formaldehyde and glutaraldehyde for protein and histological analysis.

Six-weeks-old male ICR mice were obtained from Orient Bio (Sungnam, Korea) and acclimatized for 1 week. For Sesn2 overexpression, ICR mice were injected with the recombinant adenovirus particles (1 x 10⁹ pfu) suspended in phosphate-buffered saline with tail vein. After 48 h, phenylhydrazine (PHZ, 60 mg/kg, i.p.) was administered to induce iron accumulation and liver injury.

In total, 90 common carp susceptible to MC-LR were obtained from Hulan Fishing Ground (Harbin, China) and acclimatized in 100 L glass aquaria (15 fish per tank) containing continuously aerated water at 23 under a 12 h light-dark cycle for 10 days prior to the experiments. Following acclimation, the fish in MC-LR treatment (M) group (45 fish in 3 tanks) were exposed to 10 ug/L of MC-LR for 15 days. The baseline mean body weights of the fish in the control (C) and M groups were 2.11 ± 0.03 and 2.12 ± 0.01 g, respectively.

Male C57BL/6 mice (8-10 weeks old and weighing 20-25 g) were purchased from Hunan Experimental Animal Center (Changsha, China). All animals were housed in a 12/12h light/dark cycle and given free access to water and food. All experimental procedures were conducted in accordance with the institutional guidelines for animal care. After a minimum of 7 days of acclimation, the mice were randomly divided into five groups. DILI model group was given rifampicin (350 mg/kg) that was dissolved in saline by gavage daily for 14 days, and the same volume of saline was given as the control. Meanwhile, the other three groups were given the same volume of rifampicin to establish drug liver injury model, and treated with different compounds in the second week as follows: ferrostatin 1 (0.6 mg/kg) was injected into the tail vein every day after 2 h of rifampicin administration; geldanamycin (HSP90 inhibitor) (0.75 mg/kg) was intraperitoneally injected 2 h after rifampicin daily; 3-methyladenine (autophagy inhibitor) (15 mg/kg) was injected into tail vein 2 h after rifampicin every day. After 2 weeks of administration, serum was collected, and then mice were sacrificed by cervical dislocation. After that, liver tissue was taken for different treatments and used for reserve.

Male C57 BL /6J mice (6-8 weeks; 18-22 g each) were procured from the Experimental Animal Centre of Shanghai SLAC. All mice were fed in laboratory in vivo facilities with ad libitum food and water, within a temperature-/humidity-regulated environment (22 ± 1 ; Rh. = 65 ± 5%), adopting a 12-h circadian cycling process. Mice fasted overnight for 12 h and were randomly divided into different groups.

Adult male and female fish were randomly assigned to 6 aquariums and acclimated to laboratory conditions for one week before DEHP exposure. There are 6 aquariums, where 3 aquariums were used for DEHP exposure as the treatment groups and 3 for control. Each aquarium was filled with 12 L of artificial seawater and 30 females and 30 males were assigned. Food residues and excrement were removed, and artificial water was renewed every day. The exposure groups were exposed to 10 ug/L DEHP, obtained by diluting the stock solution, and the control groups were treated with DMSO as a solvent control, in which the DMSO content did not exceed 0.01% (v/v).

Male C57BL/6 mice (7 weeks old) were purchased from Koatech Co. (Animal Breeding Center, Pyongtaek, Korea). Animals were kept on a 12 h light/dark cycle in a specific pathogen-free area with food and water freely available in the animal facility for 1 week before the experiment. All experimental animals were randomly separated into five groups as follows: Saline, LPS (1 g/kg) + D-GalN (400 mg/kg), LPS/D-GalN + YA (10 mg/kg), LPS/D-GalN + YA (50 mg/kg), and LPS/D-GalN + silymarin (25 mg/kg). YA and silymarin were pre-administered for 10 days before LPS/D-GalN by oral gavage. LPS/D-GalN was injected intraperitoneally. Blood and tissues were collected 6 h after LPS/D-GalN injection.

Female nu/nu mice aged 4-5 weeks were obtained from Charles River. Luciferase expresing-OVCAR-8 cells were harvested by trypsinization. Subsequently, cells were washed three times with cold PBS and suspended in a 1:1 mixture of PBS and Matrigel (Corning). Each mouse was inoculated subcutaneously with 5 x 10⁶ cells. When tumor volume reached approximately 50 mm³, mice were randomly divided into indicated groups. 20 mg PACMA31 per kg body weight (10% DMSO, 30% PEG-4000, 60% Saline); 40 mg regorafenib per kg body weight (Saline); or 20 mg PACMA31 plus 40 mg regorafenib per kg body weight daily. PACMA31 was intraperitoneally injected and regorafenib was orally administered.

Female nu/nu mice aged 4-5 weeks were obtained from Charles River. Luciferase expresing-OVCAR-8 cells were harvested by trypsinization. Subsequently, cells were washed three times with cold PBS and suspended in a 1:1 mixture of PBS and Matrigel (Corning). Each mouse was inoculated subcutaneously with 5 x 10⁶ cells. When tumor volume reached approximately 50 mm³, mice were randomly divided into indicated groups. 20 mg PACMA31 per kg body weight (10% DMSO, 30% PEG-4000, 60% Saline); 40 mg regorafenib per kg body weight (Saline); or 20 mg PACMA31 plus 40 mg regorafenib per kg body weight daily. PACMA31 was intraperitoneally injected and regorafenib was orally administered.

Male BALB/c mice (8-week-old, 20-22 g) were purchased from Guangdong Medical Laboratory Animal Center (Guangzhou, China). The experimental animals were fed adaptively for one week in the Experimental Animal Center of Guangdong Pharmaceutical University (Guangzhou, China). Feeding conditions were set at 26 , humidity 65% and a lightdark cycle for 12 hours. All animal experiments were performed following the Guide for the Care and Use of Laboratory Animals, and the procedures were approved by the Research Ethical Committee of Guangdong Pharmaceutical University (gdpulacspf2020007).

The mice were treated with intraperitoneal administration (i.p.) of oil (control group) or a mixture of CCl4 (50%) and oil (50%) at a dosage of 2 ml/kg body weight. In the bicyclol-treated group, mice accepted administration of 200 mg/kg (using 0.5% carboxymethyl cellulose as solvent) by gavage three times a day 1 h before CCl4 exposure, while other groups accepted vehicles of the equal volume. Fer-1 was prepared in DMSO (5 mg/kg), andi.p. injected into mice once 1 h before CCl4 exposure. The dosage of bicyclol was consistent with our previous work. The mice were then sacrificed to collect liver and serum samples after 24 or 48 h.

C57BL/6J male mice aged 8 weeks were purchased from Charles River Laboratories International, Inc., and housed in a specific pathogen-free animal facility. DMSO or DSF (21 mg/kg) was injected intraperitoneally into mice for 0.5 h, followed by ConA injection via the tail vein at 15 mg/kg. Mice were sacrificed at 24 h post ConA injection. Liver and blood samples were collected at this time point for H&E staining, IHC staining, and measurement of AST/ALT (Dian Diagnostics Co., Ltd).

All mice were randomly divided into a 2 x 2 factorial arrangement, fed diets containing 40 mg/kg or 5000 mg/kg FeSO4 (the basis of the diet was AIN-93), and gavaged with PBS or 50 mg EGCG/kg body weight per day, respectively. The experiment lasted for 6 weeks, including a 1-week adaptation and a 3-week EGCG gavage; then, all mice were euthanized.

A total of 40 male SD rats (180~200 g, 6~8 weeks) were purchased from the CMU experimental animal center. The rats were randomly divided into four groups: control (CON) group (normal diet rats were injected with equal volume of normal saline through caudal vein once a week, n = 10), SchB group (SchB diet rats, 50 mg/kg/day, were injected with equal volume of normal saline through caudal vein once a week, n = 10), THP group (normal diet rats were injected with 3 mg/kg/day THP through caudal vein once a week, n = 10), and SchB+THP group (SchB diet rats, 50 mg/kg/day, were injected with 3 mg/kg/day THP through caudal vein once a week, n = 10). CON and THP rats were fed an AIN-76A feed (12.4% fat, 68.8% carbohydrate, and 18.8% protein). SchB and SchB+THP rats were fed an SchB feed (approximately 0.5 SchB was added into AIN-76A feed). After conversion, 0.5 SchB in feed = 50 mg/kg in rats.

Six-week-old male C57BL/6J mice (18-20 g) were obtained from Zhejiang Vital River Laboratory (Zhejiang, China). 32 mice were divided randomly into 4 groups: Saline group (CONT), 25 mg/kg/day ACR group (ACR), 25 mg/kg/day ACR with a low dose of 25 mg/kg/day QCT group (ACR + QCT (L)), and 25 mg/kg/day ACR with a high dose of 50 mg/kg/day QCT group (ACR + QCT (H)), 8 animals in each group.

All mice were randomly divided into a 2 x 2 factorial arrangement, fed diets containing 40 mg/kg or 5000 mg/kg FeSO4 (the basis of the diet was AIN-93), and gavaged with PBS or 50 mg EGCG/kg body weight per day, respectively. The experiment lasted for 6 weeks, including a 1-week adaptation and a 3-week EGCG gavage; then, all mice were euthanized.

All mice were randomly divided into a 2 x 2 factorial arrangement, fed diets containing 40 mg/kg or 5000 mg/kg FeSO4 (the basis of the diet was AIN-93), and gavaged with PBS or 50 mg EGCG/kg body weight per day, respectively. The experiment lasted for 6 weeks, including a 1-week adaptation and a 3-week EGCG gavage; then, all mice were euthanized.

Six-week-old male C57BL/6J mice (18-20 g) were obtained from Zhejiang Vital River Laboratory (Zhejiang, China). 32 mice were divided randomly into 4 groups: Saline group (CONT), 25 mg/kg/day ACR group (ACR), 25 mg/kg/day ACR with a low dose of 25 mg/kg/day QCT group (ACR + QCT (L)), and 25 mg/kg/day ACR with a high dose of 50 mg/kg/day QCT group (ACR + QCT (H)), 8 animals in each group.

Three-week-old specific pathogen-free ICR (Institute of Cancer Research) male mice (weights of 18-22 g) were provided by Liaoning Changsheng Biotech Co. Ltd. The mice were housed under conditions at 22 ± 2 with 35-65% humidity and a light/dark cycle of 12 h/12 h in the cage. The animals were quarantined for a week before formal experiments, then randomly divided into seven groups: vehicle control group (Vcon), control group (Con), 5 mg/kg BW/d Lyc group (Lyc), 500 and 1000 mg/kg BW/d DEHP group (D5 and D10, respectively), DEHP + Lyc group (DL5 and DL10, respectively) (n = 20). The animals were exposed to DEHP via oral gavage, which lasted for 28 d, and then sacrificed after being anesthetized.

ALI induction was performed in 6-8-week-old age-matched C57BL/6J male mice (n = 10-12 per group) by intraperitoneal injection of 3 mL/kg CCl4 in coconut oil. Control and negative control mice were injected with PBS and coconut oil, respectively. At 6 h after injection of CCl4, mice were divided into three groups: CCl4 group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + MSC group, injected with 5 x 10⁵ MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + Fer-1 group, intraperitoneally injected with ferrostatin-1 (Fer-1, a ferroptosis inhibitor, 2.5 umol/kg body weight). Erastin, intraperitoneal injection of erastin (a ferroptosis inducer, 30 mg/kg body weight) twice every other day, and then the mice were divided into two groups (n = 10-12 per group): Erastin group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; Erastin + MSC group, injected with 5 x 10⁵ MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through the tail vein.

ALI induction was performed in 6-8-week-old age-matched C57BL/6J male mice (n = 10-12 per group) by intraperitoneal injection of 3 mL/kg CCl4 in coconut oil. Control and negative control mice were injected with PBS and coconut oil, respectively. At 6 h after injection of CCl4, mice were divided into three groups: CCl4 group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + MSC group, injected with 5 x 10⁵ MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; CCl4 + Fer-1 group, intraperitoneally injected with ferrostatin-1 (Fer-1, a ferroptosis inhibitor, 2.5 umol/kg body weight). Erastin, intraperitoneal injection of erastin (a ferroptosis inducer, 30 mg/kg body weight) twice every other day, and then the mice were divided into two groups (n = 10-12 per group): Erastin group, injected with 100 uL PBS (supplemented with 2% mouse serum) through a tail vein; Erastin + MSC group, injected with 5 x 10⁵ MSCs suspended in 100 uL PBS (supplemented with 2% mouse serum) through the tail vein.