Abstract Introduction Introduction: Peyronie’s disease (PD) is an acquired fibrotic condition of the penis caused by microtrauma, leading to a dysregulated inflammatory response and the formation of fibrotic plaques in the tunica albuginea. This results in penile curvature, pain, and psychological distress, often impairing sexual function. Current treatments for PD have significant limitations: oral therapies show limited efficacy on curvature, and more effective invasive options such as collagenase Clostridium histolyticum carry high costs and potential adverse effects. This underscores an urgent need for novel therapeutic approaches that target the underlying pathophysiology of the disease. Objective Objective: To present a comprehensive overview and critical analysis of the most promising emerging therapies for PD, exploring their mechanisms of action, current development status, and the clinical challenges for their implementation. Methods Methods: A literature search was conducted in electronic databases (PubMed, Scopus, Web of Science, and ClinicalTrials.gov). Search terms combined “Peyronie’s disease” with keywords including “gene therapy,” “stem cell,” “shock wave therapy,” and “Tadalafil.” Boolean operators (AND/OR) were used to refine searches (e.g., “Peyronie’s disease” AND (“shock wave therapy” OR “Li-ESWT”)). The search was limited to original articles, systematic reviews, and meta-analyses published between 2024 and 2025 to ensure contemporary relevance. Seminal studies outside this range (e.g., on hyperthermia) were also included if fundamental for understanding emerging therapies. Articles were selected based on their focus on novel or investigational therapies and their contribution to understanding the molecular basis of PD. Opinion pieces, editorials without original data, and non–peer-reviewed studies were excluded. Each article was critically analyzed to determine its contribution to key topics of this review, such as the efficacy of emerging therapies, their mechanisms of action, and the challenges for clinical implementation. Results Several promising therapeutic avenues were identified. Cell-based therapies, such as Mesenchymal Stem Cells (MSCs) and Platelet-Rich Plasma (PRP), have shown potential for tissue regeneration and immunomodulation in preclinical models, though clinical evidence remains preliminary. Key challenges include a lack of standardized protocols and limited long-term safety data. Gene therapies targeting the central fibrotic mediator Transforming Growth Factor-beta 1 (TGF-β1) have demonstrated effectiveness in suppressing fibrosis and even inducing plaque regression in animal models, representing a highly precise approach to treating the underlying disease process. Furthermore, low-intensity extracorporeal shock wave therapy (Li-ESWT) has been consolidated as an effective treatment for penile pain in the acute phase of PD, though its impact on curvature is modest; recent studies highlight a trend toward multimodal therapy (e.g., combining Li-ESWT with PRP) to enhance efficacy. Other novel approaches, such as hyperthermia with infrared laser, have shown initial promise in reducing plaque size. Conclusions The future of PD management is shifting from symptom-focused treatments toward personalized, multimodal, and molecularly targeted therapies. While many emerging therapies are still in early stages of development, their potential to address the root cause of fibrosis is significant. Overcoming challenges related to standardization, long-term safety, and regulatory hurdles will be crucial for these innovative treatments to become part of standard clinical practice. Disclosure No
Sarnoski et al. (Mon,) studied this question.