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Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy
Xixi Han1,2, Jingwen Kong2, Baike Liu1
1Department of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, People's Republic of China.
Background:
Membranous nephropathy (MN) is the leading cause of adult nephrotic syndrome with rising global incidence. A substantial proportion of patients progress to end-stage renal disease. Multiple programmed cell death (PCD) pathways-including apoptosis, pyroptosis, ferroptosis, and autophagy-are activated by complement-dependent and -independent pathogenic factors, collectively driving podocyte injury and MN progression. Current immunosuppressive therapies are limited by adverse reactions and variable responses. Traditional Chinese medicine (TCM), characterized by multi-component, multi-target, and multi-pathway regulation, shows therapeutic advantages in MN.
Purpose:
To systematically review the regulatory mechanisms of PCD in MN, summarize the molecular basis of TCM interventions targeting PCD, and identify current research limitations and future directions.
Methods:
This narrative review systematically elaborates the regulatory association between PCD and podocyte injury in MN. Literatures were systematically retrieved from PubMed, Embase and China National Knowledge Infrastructure (CNKI) from the establishment of each database to May 2026, and 41 preclinical studies exploring TCM modulation of PCD in MN were included after strict screening.
Results:
Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction. TCM can regulate PCD through core signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1), mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase/forkhead box O1 (JNK/FoxO1), and PTEN-induced kinase 1/Parkin (PINK1/Parkin), while simultaneously intervening in non-PCD pathological processes including inflammation, oxidative stress, and renal fibrosis. Clinical evidence further indicates that TCM or combined with conventional therapy can elevate MN remission rates and decrease adverse reactions.
Conclusion:
PCD represents a core mechanism mediating podocyte injury and MN progression. TCM effectively modulates PCD imbalance through multi-target regulation, demonstrating prominent clinical efficacy and safety. These findings provide a theoretical basis and translational direction for developing high-efficacy, low-toxicity therapeutic strategies for MN.
Insights
Programmed cell death (PCD) drives membranous nephropathy (MN) progression. Traditional Chinese Medicine (TCM) effectively regulates PCD pathways, offering a promising therapeutic strategy for MN with improved efficacy and safety.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Membranous nephropathy (MN) is a primary cause of adult nephrotic syndrome, often leading to end-stage renal disease.
- Multiple programmed cell death (PCD) pathways, including apoptosis, pyroptosis, ferroptosis, and autophagy, are implicated in podocyte injury and MN progression.
- Current immunosuppressive therapies for MN have limitations, including adverse effects and variable patient responses.
Purpose of the Study:
- To systematically review the regulatory mechanisms of PCD in MN.
- To summarize the molecular basis of Traditional Chinese Medicine (TCM) interventions targeting PCD in MN.
- To identify current research limitations and future directions for MN treatment.
Main Methods:
- A narrative review systematically elaborating the association between PCD and podocyte injury in MN.
- Literature retrieval from PubMed, Embase, and CNKI databases up to May 2026.
- Inclusion of 41 preclinical studies on TCM modulation of PCD in MN.
Main Results:
- Complement-dependent and -independent pathways activate multiple PCD pathways, causing podocyte injury in MN.
- TCM regulates PCD via key signaling pathways (PI3K/Akt/mTOR, Nrf2/HO-1, MAPK, JNK/FoxO1, PINK1/Parkin) and addresses inflammation, oxidative stress, and fibrosis.
- Clinical data suggest TCM improves MN remission rates and reduces adverse reactions when used alone or with conventional therapies.
Conclusions:
- PCD is a central mechanism in podocyte injury and MN progression.
- TCM demonstrates multi-target regulatory efficacy and safety in modulating PCD imbalance for MN treatment.
- Findings support TCM as a basis for developing highly effective, low-toxicity therapies for MN.
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