BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive therapy for early gastrointestinal neoplasms, but patients may experience reduced functional capacity and delayed recovery post-procedure. Prehabilitation, has shown benefits in major surgery by improving physical fitness and recovery. We hypothesized that a structured prehabilitation regimen before ESD would enhance postoperative functional recovery and patient outcomes compared to standard care. METHODS: Single-center, assessor-blinded randomized controlled trial of 100 adults undergoing elective ESD, randomized to 4-week prehabilitation (supervised aerobic/resistance training 3x/week, individualized nutrition with protein supplementation, and psychological support) or usual care (standard instructions without structured exercise or nutrition). The primary outcome was change in six-minute walk distance (6MWD) from baseline to 1 month. Secondary outcomes included handgrip strength, quality of life (SF-36), psychological health (HADS), postoperative complications, length of stay, and 90-day readmissions. RESULTS: Baseline characteristics were similar between groups. At 1-month post-ESD, six-minute walk distance had decreased in both groups with no significant between-group difference (mean change from baseline -40.9 m in prehabilitationversus -53.3 m in controls, p = 0.439). By 3 months, the prehabilitation group surpassed their baseline walking distance (18.9 m), whereas controls remained below baseline (- 14.1 m), indicating superior functional recovery with prehabilitation (p = 0.022). Prehabilitation also led to greater improvements in early postoperative strength and patient-reported outcomes. At 1 month, handgrip strength increased more in the prehabilitation group (mean 5.6 kg versus 4.1 kg, p = 0.001). Anxiety symptoms improved significantly with prehabilitation (HADS anxiety score change -1.17 versus -0.22, p = 0.003), with a parallel significant reduction in depression scores (p = 0.002). Prehabilitation patients reported higher gains in mental quality-of-life by 3 months (SF-36 mental component +15.4 versus +11.4 points, p < 0.001). There were no significant differences in perioperative safety outcomes, average hospital stay, and 90-day readmission rates. CONCLUSIONS: A 4-week multimodal prehabilitation program for ESD patients significantly improved postoperative functional capacity and psychological well-being without increasing complication rates or hospital stay. Prehabilitation is a safe and effective strategy to enhance recovery and patient-centered outcomes in ESD. CLINICAL TRIAL REGISTRATION: This trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR) (registration number: ChiCTR2500103062) on May 23, 2025. LEVEL OF EVIDENCE: Level I (Randomized Controlled Trial).

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