Lupenone regulates LOXL2-mediated PANoptosis signaling through E3 ubiquitin ligases RNF168 to improve radiation-induced lung injury.

BACKGROUND

Radiation-induced lung injury (RILI) is one of the most prevalent complications of thoracic radiotherapy (RT). Lupenone (LUP) is a bioactive compound isolated from Acacia catechul.f. Willci. and is believed to be capable of treating respiratory and lung diseases.

OBJECTIVE

This research examined the mechanism by which LUP modulates the ubiquitination and degradation of LOXL2 protein in radiation-induced lung injury (RILI), as well as its effect on the LOXL2-mediated ZBP1-PANoptotic pathway.

MATERIALS AND

METHODS

RILI mouse models and TGF-β-induced primary lung fibroblasts were established to evaluate the protective effect of LUP. The experiment evaluated the expression of LOXL2 and PANoptosis markers. RNA sequencing is used to analyze RILI related signaling pathways. The influence of LUP on primary lung fibroblasts was investigated, and the ubiquitination processes mediated by RNF168.

RESULTS

LUP significantly reduced collagen fiber deposition, EMT levels, and lung immune cell infiltration in RILI mice. RNA sequencing revealed significant alterations in PANoptosis pathway in RILI mouse lung tissues. LUP inhibited LOXL2 levels and attenuated ZBP1-mediated PANoptosis. LUP bound to LOXL2, and RNF168 was identified as a regulator of LOXL2, facilitating K63-linked polyubiquitination and subsequent degradation of LOXL2. LUP decreased ECM, EMT, and inflammation markers while promoting PANoptosis by downregulating LOXL2 in lung fibroblasts. LOXL2 siRNA attenuated the regulatory effects of LUP on these functions.

CONCLUSIONS

We demonstrate the therapeutic potential of LUP against RILI via a novel pathway involving RNF168-dependent LOXL2 degradation and subsequent suppression of ZBP1-PANoptosis. This identifies LUP as a candidate drug and uncovers a key regulatory axis for RILI.