Melatonin ameliorates circadian rhythm disruption induced erectile dysfunction by inhibiting oxidative stress mediated pyroptosis via Nrf2/HO‑1 axis

Melatonin partly restored erectile function in rats with disrupted light cycles by blocking a cell-death pathway

Journal: International Journal of Molecular Medicine | Published: 2026-06-11 | Type: Journal Article | PMID: 42272256 Authors: Yang Qingtao, Li Wei, Yu Qi, Shi Jiang, Yang Lu, Qiao Jun, Wei Xi, Gu Changshi, Sun Fa, Li Tao (Department of Urology, The Affiliated Hospital of Guizhou Medical University; West China Hospital, Sichuan University) Funding/COI: Funding source not listed. Authors declare no competing interests.

Summary

Researchers disrupted the light-dark cycle in 24 Sprague-Dawley rats (2h light:2h dark for 4 weeks) to model circadian rhythm disruption, then gave some of them daily melatonin injections. Disrupted rats had substantially worse erectile responses than controls, and melatonin partially reversed this — the proposed mechanism runs through reduced oxidative stress and a specific inflammatory cell-death pathway (NLRP3-mediated pyroptosis) in penile tissue and endothelial cells.

Claims

• Circadian disruption dropped maximal intracavernous pressure (mICP) from 76.82±3.81 mmHg (control) to 44.91±7.51 mmHg (P<0.0001)
• Low-dose melatonin (5 mg/kg/day) raised mICP to 57.03±2.03 mmHg (P=0.0008); high-dose (10 mg/kg/day) raised it to 66.15±2.49 mmHg (P<0.0001) — still below control
• mICP/mean arterial pressure ratio fell from 0.64±0.03 (control) to 0.38±0.07 with disruption, and rose to 0.50±0.02 (low dose) and 0.59±0.05 (high dose) with melatonin
• Disruption reduced eNOS, NO, and cGMP in penile tissue; melatonin partially restored these
• In LPS-treated human umbilical vein endothelial cells (HUVECs) used as an in vitro stand-in for circadian stress, melatonin (800 μM) reduced markers of oxidative stress and NLRP3-driven pyroptosis via the Nrf2/HO-1 pathway
• A reactive oxygen species inhibitor (NAC) blocked LPS-induced pyroptosis in HUVECs, supporting the proposed oxidative stress → pyroptosis → endothelial damage sequence

Study Quality

This is a mechanistic animal and cell-culture study, not a clinical trial, and should be read as hypothesis-generating rather than practice-changing. Group sizes were small (6 rats per group, 24 total across four groups), which is standard for this kind of bench mechanistic work but leaves little room to detect subtler effects or rule out chance findings, especially with four comparison groups run on a single cohort. The in vitro portion used an immortalized HUVEC line (HUVEC-SV40) with LPS exposure as a proxy for circadian disruption — a reasonable but indirect model, since LPS-induced inflammation and light-cycle disruption are not the same stressor mechanistically.

The core measurements (intracavernous pressure, eNOS/NO/cGMP levels, histology) are standard and appropriately quantified with reported p-values. The dose-response pattern (low vs. high melatonin dose) and the NAC rescue experiment strengthen the mechanistic case. However, melatonin never fully restored function to control levels at either dose, a point the abstract's framing as "effectively counteracts this pathology" somewhat overstates.

Red Flags

• Small sample size (n=6 per group) for a four-arm rodent study
• No funding source listed at all, which is unusual and not explained
• Mechanism validated only in an immortalized endothelial cell line under LPS stimulation, not primary penile tissue cells or a second in vitro model
• Melatonin doses used (5-10 mg/kg/day IP) are far above typical human oral melatonin dosing and were injected, not oral — translation to humans is not established
• Abstract language ("promising therapeutic strategy," "solid theoretical foundation") edges toward promotional framing for animal-only data
• No blinding of outcome assessors mentioned in the excerpted methods

Strengths

• Combined in vivo (rat) and in vitro (HUVEC) approaches targeting the same pathway
• Dose-response design (low and high melatonin doses) rather than a single dose
• Mechanistic rescue experiment (NAC blocking ROS) supports the proposed causal chain rather than just correlation
• Reported actual pressure values, ratios, and p-values rather than vague "significant improvement" language
• Body weight monitored to rule out general toxicity/metabolic confounding

Verdict

A carefully constructed rodent mechanism study showing melatonin partially — not fully — restores erectile function after circadian disruption, with a plausible Nrf2/HO-1 to NLRP3-pyroptosis pathway. Worth attention as basic-science mechanism work, not as evidence that melatonin treats erectile dysfunction in shift workers or anyone else; the small sample size, animal-only design, and unlisted funding source mean this is early-stage groundwork, not clinical guidance.