Tirzepatide

Tian Y, et al. International Immunopharmacology, 2025, 146, 113877.

This study compared the efficacy of tirzepatide with semaglutide and insulin in alleviating diabetic nephropathy (DN) and explored its underlying mechanisms. At one-third the dose of semaglutide, tirzepatide achieved comparable reductions in blood glucose, body weight, and urine albumin-to-creatinine ratio (UACR) while enhancing antioxidative stress markers. Insulin treatment, by contrast, failed to restore UACR effectively. RNA-seq analysis revealed that tirzepatide significantly enriched the PI3K-AKT signaling pathway in renal tissues. In vitro studies using mouse podocyte cell-5 exposed to high glucose confirmed that tirzepatide alleviated oxidative stress via the PI3K-AKT pathway, an effect reversed by PI3K inhibitors.
These findings highlight the potential of tirzepatide as a novel therapeutic option for DN, offering dual benefits of glycemic control and renal protection. By targeting oxidative stress and modulating the PI3K-AKT pathway, tirzepatide addresses critical mechanisms underlying DN progression, paving the way for innovative treatment strategies.

Kong W, et al. Gynecologic Oncology, 2024, 191, 116-123.

Tirzepatide has demonstrated significant anti-obesity and anti-tumorigenic properties in a preclinical mouse model of endometrioid endometrial cancer (EC). This study investigated tirzepatide's effects on metabolic, immune, and tumor growth pathways in lean and obese phenotypes.
Treatment with tirzepatide for four weeks led to significant weight loss of 20.1% in obese mice and 16.8% in lean mice. Tirzepatide reversed obesity-associated metabolic disturbances, including improved serum levels of adiponectin, leptin, gastric inhibitory polypeptide, and C-reactive protein. In obese mice, tirzepatide inhibited tumor growth by modulating ErbB signaling and glycolysis/gluconeogenesis, while in lean mice, it increased O-linked glycosylation biosynthesis and phospholipase D signaling pathways. The study highlights tirzepatide's ability to target obesity-induced metabolic dysfunctions and EC tumor progression through distinct mechanisms tailored to metabolic states.

Xia Y, et al. International Immunopharmacology, 2024, 143(2), 113499.

Tirzepatide has shown remarkable potential in addressing metabolic disturbances associated with obesity and type 2 diabetes mellitus (T2DM). This study examined tirzepatide's effects on adipose tissue macrophages (ATMs), inflammation, and insulin resistance in obese mouse models.
Obese mice fed a high-fat diet were treated with tirzepatide (1.2 mg/kg) twice weekly for 12 weeks. Tirzepatide significantly reduced the infiltration of pro-inflammatory M1 macrophages into adipose tissue, thereby decreasing inflammatory cytokine levels. This modulation of the ATM phenotype enhanced insulin sensitivity, demonstrating tirzepatide's therapeutic efficacy in metabolic regulation. Mechanistically, tirzepatide activated the ERK signaling pathway and promoted apoptosis in M1 macrophages, effectively mitigating adipose tissue inflammation.These findings highlight tirzepatide's dual role in targeting obesity-associated inflammation and metabolic dysfunction.

Yang S, et al. Peptides, 2024, 179, 171271.

Tirzepatide has demonstrated neuroprotective effects in a preclinical Alzheimer's disease (AD) model using APP/PS1 mice. This study investigated its potential to mitigate amyloid-β (Aβ)-induced neuronal damage and enhance glucose metabolism.
APP/PS1 mice were treated with tirzepatide (10 nmol/kg, intraperitoneally, once weekly) for 8 weeks. Tirzepatide significantly reduced amyloid plaques, GFAP protein expression, and neuronal apoptosis in the cortex while also downregulating GLP-1R. Additionally, it improved hypothalamic mRNA expression of GLP-1R, SACF1, ATF4, and Glu2 subunits, indicating modulation of brain glucose metabolism. In the cortex, tirzepatide upregulated key metabolic enzymes, including glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase. Furthermore, tirzepatide enhanced mitochondrial function by regulating reactive oxygen species production and mitochondrial membrane potential in astrocytes, ultimately improving ATP levels. While these benefits were notable, tirzepatide did not affect anxiety or cognitive function in APP/PS1 mice during the treatment period.

Chen L, et al. Peptides, 2024, 178, 171245.

Tirzepatide demonstrates potent cardioprotective properties against doxorubicin (DOX)-induced cardiotoxicity. This study evaluated its efficacy and underlying mechanisms in both in vivo and in vitro models.
DOX-induced cardiotoxicity was established in male C57BL/6 mice through weekly intraperitoneal injections of DOX (4 mg/kg) for four weeks. Tirzepatide (1.35 mg/kg) was administered subcutaneously daily for two weeks following the initial DOX exposure. Parallel studies in H9c2 cardiomyocytes investigated its cellular effects.
Tirzepatide significantly reduced oxidative stress, inflammation, and cardiac injury induced by DOX. Mechanistic investigations revealed that activation of the PI3K/Akt signaling pathway was essential for its cardioprotective effects. Pharmacological inhibition of this pathway with LY294002 abolished Tirzepatide's benefits, confirming the pivotal role of PI3K/Akt signaling. Additionally, Tirzepatide preserved cardiac function, normalized body weight, and maintained heart-to-body weight ratios. These outcomes highlight its ability to counteract DOX-induced damage through modulation of oxidative stress and inflammatory pathways.