PANoptosis, a newly characterized form of inflammatory programmed cell death that integrates multiple cell death modalities, offers distinct advantages in both potent tumor cell killing and activation of antitumor immunity. However, strategies that can effectively induce PANoptosis in tumor cells remain scarce. Herein, we constructed a tumor microenvironment-responsive nanoplatform (HA-MnO2-FTY720@CaO2, HMFC) comprising a CaO2 core and a MnO2 shell, loaded with fingolimod (FTY720) and surface-functionalized with hyaluronic acid (HA) for CD44-mediated targeting. Under the mildly acidic and glutathione (GSH)-rich conditions of the tumor microenvironment (TME), the MnO2 shell degrades, liberating FTY720 and exposing the CaO2 core. The CaO2 subsequently decomposes to release Ca2+ and H2O2. FTY720 inhibits Transient Receptor Potential Melastatin 7 (TRPM7) channels, disrupting Ca2+/Mg2+ homeostasis and thereby provoking severe calcium overload. Simultaneously, MnO2 depletes GSH and, together with CaO2-derived H2O2, promotes a Fenton-like reaction that generates abundant reactive oxygen species (ROS), thereby disrupting intracellular redox homeostasis. In addition, Mn2+ released from MnO2 degradation activates the cGAS–STING pathway, further contributing to DC maturation and antitumor immunity. This orchestrated immune response markedly suppresses tumor growth and when combined with anti-PD-L1 therapy, induces a pronounced abscopal effect. Together, our results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO2-induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.
Aiyang Tong, Yang Zhou, Yang Ding et al.· Materials Today Bio· 0 citations
BACKGROUND
Polynucleotide phosphorylase 1 (PNPT1) functions as a crucial mitochondrial enzyme; nevertheless, its potential genetic correlation with osteoporosis and its specific regulatory impact on osteoclastogenesis remain to be elucidated.
METHODS
We executed a two-sample Mendelian randomization (MR) strategy to interrogate the causal link connecting PNPT1 expression to osteoporosis risk. For in vivo substantiation, we utilized both an ovariectomized (OVX) murine model and an adeno-associated virus (AAV)-driven overexpression system. Extensive in vitro assays employing RANKL-stimulated RAW264.7 macrophages were conducted to evaluate osteoclast differentiation, mitochondrial dynamics, autophagic flux, and intracellular oxidative stress through molecular and morphological analyses.
RESULTS
MR evaluations pinpointed genetically predicted elevated PNPT1 expression as a potential genetic risk factor for osteoporosis. In vivo observations revealed a significant surge of PNPT1 within the osteoclast precursors of OVX subjects. In vitro, the ectopic overexpression of PNPT1 significantly enhanced osteoclastogenesis and bone degradation while simultaneously triggering severe mitochondrial depolarization alongside the accumulation of reactive oxygen species (ROS). On the contrary, targeted Pnpt1 silencing markedly suppressed osteoclast maturation. Mechanistic probes demonstrated that PNPT1 disrupted autophagic flux, marked by p62 accumulation. Notably, even with a compensatory transcriptional rise in Nrf2 mRNA, PNPT1 overexpression provoked a marked downregulation of Nrf2 and xCT proteins, suggesting a potent post-transcriptional suppression of the cellular antioxidant shield. This uncoupling invariably precipitated sub-lethal lipid peroxidation that amplifies osteoclastogenic signaling. Concordantly, AAV-mediated systemic PNPT1 amplification aggravated trabecular bone deterioration in vivo.
CONCLUSION
Guided by our MR findings and validated through our functional models, PNPT1 emerges as a potential genetic risk factor for osteoporosis. By inciting mitochondrial damage, provoking ROS buildup, and decoupling the protective autophagy-Nrf2/xCT axis, PNPT1 promotes osteoclastogenesis, thereby introducing a promising immunopharmacological target for restraining pathological bone resorption.
ChengYan Liu, Xinlin Nie, Fangze Xing et al.· International Immunopharmaco...· 0 citations