Substantial research into cellular senescence mechanisms has led to the development of FOXO4-DRI, a senolytic compound also known as the IT-Inhibitor peptide. This bioactive peptide shows promising anti-aging properties.
In senescent cells, for instance, FOXO4 binds to p53, forming a complex known as FOXO4-p53 aggregates. This complex acts as an inhibitor of apoptosis initiation. Do đó, this interaction extends the lifespan of cellular senescence and leads to their accumulation over time.
Đáng chú ý, FOXO4-DRI does not directly target FOXO1, FOXO3, or p53 proteins. Thay vì, it specifically interacts with FOXO4’s binding site within the FOXO4-p53 complex. This interaction promotes the complex’s dissociation, releases p53, and thereby re-activates p53-induced apoptosis, all while sparing normal cells from side-effects.
Several reports demonstrate the potent efficacy of FOXO4-DRI in selectively killing senescent cells. Hơn nữa, studies indicate that FOXO4-DRI reverses age-associated physiological decline: it increases physical endurance and motor performance, restores renal function and hair growth, and thereby slows down age-related tissue decay. Ví dụ, aged mouse models clearly show these benefits. Additionally, FOXO4-DRI reduces chronic inflammation and tissue damage in the post-chemotherapy microenvironment, thus improving the quality of life and promoting long-term health in cancer patients.
Sự liên tiếp
H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH
Số CAS
2460055-10-9
Công thức phân tử
C228H388N86O64
Trọng lượng phân tử
5358.05
Research Of Foxo4-dri Benefits
1.Selective Induction of Senescent Cell Apoptosis
The primary mechanism of FOXO4-DRI involves the specific stimulation of programmed cell death in senescent cells. Đây, p53 operates as a trans-activating factor for pro-apoptotic genes, inducing apoptosis. Tuy nhiên, under normal physiological conditions, the FOXO4-p53 complex represses this apoptotic function.
By competing for p53 binding, FOXO4-DRI disrupts the FOXO4-p53 interaction. This disruption initiates the intrinsic apoptosis pathway specifically in senescent cells.
In aged mice, treatment with FOXO4-DRI led to hair regrowth comparable to middle-aged mice and significantly enhanced motor performance.
2.Quality of Life for Cancer Patients
Researchers are exploring FOXO4-DRI as a potential adjuvant drug to improve the quality of life for cancer patients after chemotherapy. While numerous anticancer agents affect tumor cells, they also cause non-specific injury to normal cells, increasing the burden of therapy-induced senescence(TIS).
Extensive studies validate that FOXO4-DRI can efficiently eliminate both spontaneous and treatment-induced senescent cells, ameliorating chemotherapy-induced frailty syndrome. For instance, a study in Cell demonstrated improved recovery and survival in chemotherapy-treated mice. These findings highlight the strong adjuvant therapeutic potential of FOXO4-DRI in oncology.
3.Ameliorating Liver Disease Pathology
In NASH(Nonalcoholic steatohepatitis) patients, senescent cells accumulate in the liver and secrete pro-inflammatory and pro-fibrotic molecules via the senescence-associated secretory phenotype (SASP), driving disease progression. Studies using a mouse NASH model found that FOXO4-DRI eliminated these hepatic senescent cells, suppressing SASP production at its source.
4.Treatment of Mice with Bleomycin-Induced Pulmonary Fibrosis
FOXO4-DRI triggers selective p53 nuclear exclusion and dissociation of the FOXO4-p53 complex. In bleomycin-induced mouse models, treatment with FOXO4-DRI decreased levels of Collagen, type I, alpha 1 (Col1a1) and α-SMA in lung tissues. This reduction suggests decreased production of extracellular matrix and inhibition of myofibroblast activation.
Although the study did not fully elucidate the precise pathway of FOXO4-DRI’s interaction with p53, it clearly demonstrated effective inhibition of fibrosis, highlighting a potential therapeutic strategy for idiopathic pulmonary fibrosis (IPF).
5.Alleviating Age-Related Hypogonadism (Testosterone Deficiency)
Male late-onset hypogonadism is an aging-related dysfunction impairing aged Leydig cells. Clearing these senescent cells can rejuvenate tissue function. Studies show that FOXO4-DRI acts specifically on human testicular Leydig cells. Administering it to aged mice improved the testicular microenvironment, preventing age-related testosterone deficiency. MỘT 2021 study reported a significant increase in serum testosterone levels in treated aged mice.
The proposed mechanism involves specific suppression of p53 nuclear localization and dissociation of the FOXO4-p53 complex, resulting in senescent-cell apoptosis. These results suggest a potential therapeutic avenue for treating age-associated testosterone reduction.
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