Salidroside Boosts Stem Cell Therapy to Reverse Premature Ovarian Failure

Premature ovarian insufficiency (POI) is a condition in which ovarian function declines before age 40, causing infertility, hormonal disruption, and significantly reduced quality of life. Ferroptosis — a regulated form of cell death driven by iron accumulation and lipid peroxidation — has emerged as a likely contributor to follicle loss in POI. Mesenchymal stem cells (MSCs) have shown promise as a regenerative treatment but are limited by poor survival in the hostile ovarian microenvironment following transplantation. This study investigated whether salidroside, the primary bioactive compound in Rhodiola rosea, could enhance MSC-based therapy for POI by improving MSC survival and amplifying their antioxidant and anti-ferroptotic actions.

Researchers isolated human umbilical cord-derived MSCs and primary rat ovarian granulosa cells (GCs). In vitro, GCs were damaged using 4-hydroxycyclophosphamide (4-HC), hydrogen peroxide, or the ferroptosis inducer erastin. Conditioned medium from salidroside-pretreated MSCs (SCM) was compared against regular MSC conditioned medium (CM) and salidroside alone. A cyclophosphamide (CTX)-induced POI rat model was then used for in vivo validation, with direct ovarian injection of PBS, salidroside, MSCs, or the combination. Outcomes included serum hormone levels (FSH, AMH, E2), follicle counts, fertility rates, lipid peroxidation markers (MDA, SOD), iron deposition (Prussian blue staining), mitochondrial morphology (electron microscopy), and Keap1/Nrf2/GPX4 pathway gene and protein expression.

Salidroside significantly promoted MSC proliferation and reduced their apoptosis under oxidative stress. In damaged GCs, SCM outperformed CM in restoring cell viability, reducing MDA, increasing SOD activity, lowering intracellular ferrous iron, and preserving mitochondrial membrane potential. In POI rats, the salidroside + MSCs combination group showed superior restoration of FSH, AMH, and estradiol levels compared to MSC monotherapy, along with higher antral and total follicle counts, fewer atretic follicles, and improved pregnancy rates. Transmission electron microscopy confirmed reduced mitochondrial damage in ovarian tissue from the combination group. Mechanistically, the combined treatment activated the Keap1/Nrf2/GPX4 axis, upregulating downstream antioxidant and anti-ferroptotic molecules, indicating a preserved redox homeostasis as the likely molecular basis for these benefits.

These findings position salidroside-enhanced MSC therapy as a dual-action strategy: salidroside protects MSCs during transplantation while also potentiating their paracrine anti-ferroptotic effects on granulosa cells. The Keap1/Nrf2/GPX4 pathway appears central to this mechanism, offering a tractable molecular target for future drug development in POI and potentially other conditions involving oxidative ovarian injury.

Important caveats apply. The study used a chemotherapy-induced POI model, which may not fully represent idiopathic or genetic POI. All in vivo work was conducted in rats, and translation to humans requires clinical validation. The long-term safety and durability of salidroside-MSC co-administration have not been assessed.