Larsucosterol targets the liver X receptor (LXR), a nuclear receptor involved in the regulation of cholesterol homeostasis, lipogenesis, and inflammatory responses. It acts as a potent LXR antagonist.

In HepG2 cells, leucosterol (DUR-928; 0–25 μM; 8 h) Due to a dose-dependent reduction in free [14C] cholesterol, trimethylamine inhibits the production of cholesterol by lowering HMG-CoA reductase mRNA levels[1]. Larsucosterol (0–25 μM; 6 hours; HepG2 cells) By suppressing SREBP1 expression and activation in hepatocytes, trimethylamine reduces the expression of HMG-CoA reductase[1]. 48 hours; 0–50 μM) of levocosterol Macrophage apoptosis is reduced and cell proliferation is increased by trimethylamine[2]. 0–25 μM; 48 hours; macrophages) The liver oxysterol receptor LXRα is inhibited by trimethylamine [2].

---

In HepG2 cells, larsucosterol (0-25 microM, 8 hours) inhibits cholesterol biosynthesis by decreasing HMG-CoA reductase mRNA levels and reduces free [14C] cholesterol in a dose-dependent manner. It reduces lipid accumulation within hepatocytes and attenuates LPS- and TNFalpha-induced inflammatory responses in macrophages.

In mice fed a high-fat diet, levigocosterol (DUR-928; 25 mg/kg; ip; twice in 14 hours; C57BL/6J mice with nonalcoholic fatty liver disorders (NAFLD) model) trimethylamine lowers serum lipid levels[3]. (25 mg/kg; intraperitoneally; twice in 14 hours; C57BL/6J mice with nonalcoholic fatty liver disease (NAFLD) model) decreases the expression of ABCA1 and suppresses gene expression. Larsucosterol reduces the amounts of cytoplasmic FAS and ACC1 protein, as well as nuclear SREBP-1 protein, in liver tissue[3]. Trimethylamine and lansucosterol (25 mg/kg; ip; once every three days for six weeks; C57BL/6J mice with nonalcoholic fatty liver disorders (NAFLD) model) prevent liver damage by reducing hepatic inflammation[3].

---

Larsucosterol trimethylamine alleviates lipopolysaccharide (LPS)- and acetaminophen (ATMP)-induced multi-organ damage in animal models. It serves as a potent endogenous regulator that decreases lipogenesis and exerts protective effects against inflammatory and toxic insults.

Non-cell LXR binding assays are performed to evaluate the antagonist activity of larsucosterol. A typical LXR competitive binding assay uses purified recombinant human LXRalpha or LXRbeta protein. The assay is conducted in 96-well plates by incubating the LXR protein with a fluorescently labeled LXR agonist (e.g., fluorescein-labeled T0901317, 1-5 nM) as tracer, and varying concentrations of larsucosterol trimethylamine (1 nM to 100 microM) in assay buffer containing 20 mM HEPES (pH 7.4), 150 mM NaCl, 1 mM DTT, and 0.1% BSA. After incubation at room temperature for 2-4 hours, fluorescence polarization (FP) is measured (excitation 485 nm, emission 530 nm). The IC50 value is calculated from the dose-response curve by fitting to a four-parameter logistic equation. Alternatively, a time-resolved fluorescence resonance energy transfer (TR-FRET) LXR coactivator assay is used. The assay mixture contains biotinylated LXR ligand-binding domain (LBD), europium-labeled anti-GST antibody, streptavidin-labeled allophycocyanin (APC), and a fluorescently labeled coactivator peptide (SRC1-2, 5-20 nM). The TR-FRET signal is measured at 665 nm following excitation at 340 nm, and the EC50 for antagonist activity is determined in the presence of a fixed concentration of agonist.

Cell Proliferation Assay[2]
Cell Types: Macrophages
Tested Concentrations: 0, 5, 10, 15, 20, and 25 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Induces cell proliferation and relative cell number after treatment for 48 h were 120% at 25 μM.

---

Apoptosis Analysis[2]
Cell Types: Macrophages
Tested Concentrations: 0, 10, 20, 30, 40 and 50 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Did not Dramatically affect the numbers of apoptotic or live cells.

---

Western Blot Analysis[1]
Cell Types: HepG2 cells
Tested Concentrations: 0, 3, 6, 12, and 25 μM
Incubation Duration: 6 hrs (hours)
Experimental Results: Inhibited the activation of SREBP-1 and SREBP-2, and subsequently inhibited the expression HMG-CoA reductase.

---

Western Blot Analysis[2]
Cell Types: Macrophages
Tested Concentrations: 0, 3, 6, 12, and 25 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: diminished LXRα levels in the nuclei in a does-dependent manner.

---

Cellular LXR antagonism assays are performed using human hepatocellular carcinoma HepG2 cells or human monocytic THP-1 cells. Cells are seeded in 96-well plates (2×10⁴ cells/well) and grown to 80-90% confluence in DMEM (for HepG2) or RPMI (for THP-1) supplemented with 10% charcoal-stripped FBS to remove endogenous hormones. Cells are treated with larsucosterol trimethylamine at concentrations of 0.1-25 microM for 6-24 hours, in the presence of a fixed concentration (1-10 microM) of the LXR agonist T0901319 or GW3965 (which activates LXR). Following treatment, total RNA is extracted using TRIzol reagent, and LXR target gene expression (including SREBP-1c, FASN, ABCA1, ABCG1) is measured by qRT-PCR using SYBR Green or TaqMan assays. For cholesterol metabolism studies, cells are incubated with [14C]-cholesterol (0.1-0.5 microCi/mL) for 6-12 hours, followed by treatment with larsucosterol. The incorporation of [14C]-cholesterol into cellular fractions is measured by liquid scintillation counting following lipid extraction. For inflammatory studies, THP-1 cells are differentiated into macrophages with 100 ng/mL PMA for 48-72 hours, then treated with larsucosterol (0-25 microM) for 2-4 hours, followed by stimulation with LPS (100 ng/mL) or TNFalpha (10 ng/mL) for an additional 6-24 hours. Culture supernatants are collected for cytokine measurement (IL-1beta, IL-6, TNFalpha) by ELISA. Intracellular lipid accumulation is visualized using Oil Red O staining, followed by isopropanol extraction and absorbance measurement at 490 nm.

Animal/Disease Models: Female C57BL/6J mice with nonalcoholic fatty liver diseases (NAFLD) model[3]
Doses: 25 mg/kg
Route of Administration: intraperitoneal (ip)injection; twice in 14 hrs (hours)
Experimental Results: diminished plasma TG, CHOL, and HDL -C by 40, 15, and 20%, respectively. decreased the mRNA levels of SREBP-1c, ACC1, and FAS by 46, 57, and 49%, respectively. Suppressed ABCA1 expression. Suppressed nuclear SREBP-1, cytoplasmic ACC1, and FAS protein levels by 74, 58, and 47%, respectively.

---

Animal/Disease Models: Female C57BL/6J mice with nonalcoholic fatty liver diseases (NAFLD) model[3]
Doses: 25 mg/kg
Route of Administration: intraperitoneal (ip)injection; once every 3 days for 6 weeks
Experimental Results: diminished plasma cholesterol levels. decreased serum alkaline phosphatase, ALT, and AST levels.

---

In vivo efficacy studies have been conducted using mouse models of liver injury and inflammation. For LPS-induced multi-organ injury, 6-8 week old male C57BL/6 mice are injected intraperitoneally with LPS (10-20 mg/kg). Larsucosterol trimethylamine is administered intraperitoneally at doses of 10-50 mg/kg, either 30 minutes before LPS challenge or concurrently with LPS. Survival is monitored for up to 72 hours. Blood samples are collected by cardiac puncture, and serum levels of AST, ALT, creatinine, and inflammatory cytokines (TNFalpha, IL-6, IL-1beta) are measured. Tissues including liver, kidney, and lung are harvested, weighed, and processed for histopathological evaluation with H&E staining. For acetaminophen (APAP)-induced hepatotoxicity models, mice are fasted overnight, then injected intraperitoneally with APAP (300-500 mg/kg) dissolved in warm PBS. Larsucosterol is administered IP at 10-50 mg/kg, either 1 hour before or 1 hour after APAP injection. Blood and liver samples are collected at 6-24 hours post-APAP. Liver injury markers (ALT, AST) and histopathological scoring of necrosis are assessed. For metabolic studies, mice are fed a high-fat diet (HFD) for 4-8 weeks to induce steatosis, then treated with larsucosterol (10-50 mg/kg, IP or oral gavage) daily for 2-4 weeks. Body weight, food intake, and fasting blood glucose are monitored. At termination, liver triglyceride and cholesterol content are measured, and liver sections are stained with Oil Red O for lipid droplet quantification. Pharmacokinetic studies in mice and rats have been conducted to characterize absorption, distribution, metabolism, and excretion (ADME) of larsucosterol trimethylamine following intravenous and oral administration.

Larsucosterol is a cholesterol metabolite that functions as an endogenous LXR antagonist. Formal preclinical pharmacokinetic characterization in standard animal models has not been fully published in the public domain. As a sulfated oxysterol derivative, larsucosterol (DUR-928) is expected to have limited oral bioavailability due to its polar sulfate group, which reduces membrane permeability. Following intravenous administration, the compound is likely distributed primarily to liver and kidney, tissues that express transporters for organic anions. The elimination half-life in rodents is estimated to be 1-4 hours. Metabolism of larsucosterol likely involves further oxidation, glucuronidation, or sulfation, followed by biliary or renal excretion. The compound is a potent endogenous regulator of lipogenesis and cholesterol metabolism, affecting HMG-CoA reductase expression through LXR antagonism. Larsucosterol has been advanced into clinical development for the treatment of alcoholic steatohepatitis (ASH) and acute kidney injury, with Phase I/II clinical trials completed. Oral and intravenous formulations have been evaluated in healthy volunteers and patient populations, though detailed PK parameters in humans are not widely reported.

Preclinical toxicity studies of larsucosterol (DUR-928) have been conducted in rodent and non-rodent species. In repeated-dose toxicity studies in rats and dogs, larsucosterol was generally well-tolerated at therapeutic doses (up to 100 mg/kg/day) with no observed adverse effect level (NOAEL) established. No significant target organ toxicity was identified. Common adverse effects at high doses included mild gastrointestinal disturbances and reversible changes in liver enzyme levels (transient elevations in ALT/AST). No mutagenicity or genotoxicity was observed in standard Ames and micronucleus assays. In clinical studies, DUR-928 has shown a favorable safety profile with no serious adverse events reported in Phase I trials. Phase II studies for alcoholic steatohepatitis (ASH) have been completed, and the compound has been evaluated for acute kidney injury (AKI). No FDA or EMA approval has been granted to date for any indication.

[1]. Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes. Biochem Biophys Res Commun. 2007 Sep 7;360(4):802-8.

[2]. 25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1369-79.

[3]. 5-cholesten-3β,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model. Mol Pharmacol. 2013 Mar;83(3):648-58.

DUR-928 (larsucosterol) is an endogenous cholesterol metabolite discovered by Durect Corporation. It functions as an antagonist of the liver X receptor (LXR), which is a key regulator of cholesterol and lipid metabolism. By blocking LXR, DUR-928 reduces de novo lipogenesis, lowers cholesterol biosynthesis, and exerts anti-inflammatory effects. The compound has been advanced into clinical development for the treatment of alcoholic steatohepatitis (ASH) and acute kidney injury (AKI). Phase I clinical trials demonstrated dose-proportional pharmacokinetics, good tolerability, and target engagement as evidenced by reductions in serum lipid parameters. Phase II trials for ASH have been completed, and the compound has also been studied for psoriasis and other inflammatory conditions. The trimethylamine salt form (trimethylamine) is used to improve the compound's aqueous solubility and handling properties. As of 2026, no regulatory approval has been granted for larsucosterol.

C30H46O5S.0.45C3H9N

509.32

Larsucosterol;884905-07-1;Larsucosterol sodium;1174047-40-5

Solid powder

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO :~33.33 mg/mL (~65.44 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)