Klotho-derived peptide preserves erectile function by limiting fibrosis, oxidative stress, and apoptosis of penile smooth muscle cells in cavernous nerve injured-rats through suppression of the TGF-β1/TGF-β type II receptor signaling.
Klotho-derived peptide just showed serious promise in a new rat study on erectile dysfunction. Researchers at Xinxiang Medical University put the peptide to work in a tough scenario: rats with cavernous nerve injuries, a common model for post-prostatectomy erectile dysfunction. The results? Klotho-derived peptide limited fibrosis, oxidative stress, and cell death in penile smooth muscle—all big factors in ED.
Eur J Pharmacol
by Xi Y, Han G, Li X et al.
“Klotho-derived peptide preserves erectile function by limiting fibrosis, oxidative stress, and apoptosis of penile smooth muscle cells in cavernous nerve injured-rats through suppression of the TGF-β1/TGF-β type II receptor signaling. Xi Y(1), Han G(2), Li X(3), Zhang X(4), Zhang S(5), Ma K(6), Zhu F(7). Author information: (1)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: 1fy2017130@xxmu.edu.cn. (2)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: guangye@126.com. (3)Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: lixiaojie@xxmu.edu.cn. (4)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: 601908885@qq.com. (5)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: m13569090760@163.com. (6)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: 976536268@qq.com. (7)Department of Urology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, China. Electronic address: 00103@xxmu.edu.cn. Patients with prostate cancer frequently complain of erectile dysfunction (ED) after radical prostatectomy (RP). Corporal fibrosis and apoptosis following cavernous nerve injury (CNI) significantly contribute to RP-induced ED. Klotho is an anti-aging protein, and Klotho-derived peptide (KP) has been introduced as an antagonist of tissue fibrosis and apoptosis. However, it is unknown whether CNI-induced functional and morphological changes in the penis. This study was designed to explore the impact of KP on CNI-induced ED. The rats were randomly divided into three groups: Sham operation, bilateral CNI with saline injection, and bilateral CNI with KP injection. Assessments of erectile function were conducted three weeks post-treatment. Penile tissues were obtained for histopathological examination. Corpus cavernosum smooth muscle cells (CCSMCs) treated with transforming growth factor-beta 1 (TGF-β1) served as an in vitro model to assess the impact of KP. Rats subjected to bilateral CNI developed severe ED. Penile tissues exhibited reduced smooth muscle abundance and nitric oxide synthase expression, alongside increased fibrosis, oxidative stress, apoptosis, and TGF-β1 signaling activation. However, KP ameliorated these functional and morphological damage. Moreover, KP exerted anti-fibrotic and anti-apoptotic effects on TGF-β1-stimulated CCSMCs by downregulating TGF-β type II receptor, which intercepted the Smad2/JNK signaling and activated the AKT pathway. Overall, KP improved CNI-induced ED and corporal remodeling. These beneficial effects were mediated by TGF-β type II receptor downregulation, which rebalanced the TGF-β1-driven Smad2/JNK activation and PI3K/AKT suppression, thereby ameliorating CCSMC dysfunction. Our results establish the potential of KP as a therapy for neurogenic ED. Copyright © 2026. Published by Elsevier B.V. Conflict of interest statement: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”
Here’s the core: After nerve injury, rats usually see smooth muscle loss, more fibrosis, and reduced nitric oxide synthase, wrecking erectile function. But the group treated with Klotho-derived peptide kept more smooth muscle, saw less tissue scarring, and preserved their erectile response. The science points to suppressed TGF-β1/TGF-β type II receptor signaling as the main mechanism. That means lower pro-fibrotic signaling, less cell death, and better tissue remodeling.
The team didn’t just stop at the animal model. They took penile smooth muscle cells into the lab and hit them with TGF-β1—typically a death sentence for these cells. Klotho-derived peptide still blocked fibrosis and apoptosis in this setting, confirming what they saw in the rats.
Key takeaway: Klotho-derived peptide directly supports penile tissue health after nerve injury, dialing down the molecular pathways that ruin function.
Researchers interested in fibrosis, nerve injury, or ED now have a new peptide to watch. The TGF-β/Smad2/JNK/AKT axis is a hot target, and this peptide looks ready to disrupt that dysfunctional signaling. For those tracking the latest in peptide therapies or looking for new research avenues, this is one to bookmark.
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