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Construction of PANoptosis-Inhibiting Carbonized Polymer Dots via Machine Learning Potential for Mitigating
Xinchen Liu1, Jiaxin Zhang2, Xiangyu Yan3
1Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, 130021, P. R. China.
Abstract:
Chemotherapy-induced nephrotoxicity, particularly acute kidney injury (AKI), is a severe complication that is driven by multiple regulated cell death (RCD) pathways. However, current nephroprotective strategies predominantly focus on apoptosis inhibition by relieving oxidative stress. PANoptosis is a newly discovered form of RCD pathway incorporating key features of pyroptosis, apoptosis, and necroptosis, providing a potential target for synergistic multi-mechanistic nephroprotection. Herein, the enhanced sampling method is introduced for molecular dynamics based on trained machine learning force fields to guide the construction of bioactive carbonized polymer dots (Lu-CDs) with specific pharmacophoric moieties of the flavonoid compound. Unlike conventional carbonized polymer dots with solely antioxidative activity, Lu-CDs demonstrate both radical scavenging and PANoptosis-inhibiting activities. In chemodrug-induced AKI mice, a very low dose of Lu-CDs can elicit prolonged renal accumulation and superior nephroprotective efficacy compared to the small-molecule flavonoid compound and the antioxidative carbonized polymer dots. The findings of this study highlight a design strategy for bioactive nanodrugs based on the machine learning force fields for molecular dynamics and propose PANoptosis inhibition as a promising approach to mitigate chemodrug-induced nephrotoxicity.
Insights
New bioactive carbonized polymer dots (Lu-CDs) inhibit PANoptosis, a cell death pathway, offering superior protection against chemotherapy-induced acute kidney injury (AKI) in mice.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Pharmacology
Background:
- Chemotherapy can cause acute kidney injury (AKI) via regulated cell death (RCD) pathways.
- Current treatments focus on apoptosis inhibition and oxidative stress, but a multi-mechanistic approach is needed.
- PANoptosis, a novel RCD pathway, presents a new therapeutic target for nephroprotection.
Purpose of the Study:
- To develop novel bioactive carbonized polymer dots (Lu-CDs) for enhanced nephroprotection.
- To investigate the efficacy of Lu-CDs in mitigating chemotherapy-induced AKI.
- To explore PANoptosis inhibition as a strategy against drug-induced kidney damage.
Main Methods:
- Utilized enhanced sampling with machine learning force fields for molecular dynamics to design Lu-CDs.
- Incorporated flavonoid pharmacophores into Lu-CDs for dual radical scavenging and PANoptosis-inhibiting activities.
- Evaluated Lu-CDs' nephroprotective effects in a mouse model of chemotherapy-induced AKI.
Main Results:
- Lu-CDs exhibited both radical scavenging and PANoptosis-inhibiting properties, unlike conventional antioxidative carbonized polymer dots.
- A low dose of Lu-CDs demonstrated prolonged renal accumulation and superior nephroprotective efficacy in mice.
- Lu-CDs outperformed both small-molecule flavonoids and antioxidative carbonized polymer dots in preventing AKI.
Conclusions:
- Machine learning-guided design of nanodrugs offers a promising strategy for targeted therapy.
- PANoptosis inhibition is an effective approach to combat chemotherapy-induced nephrotoxicity.
- Lu-CDs represent a novel therapeutic candidate for preventing AKI.
