Lactate attenuates PANoptosis and enhances ZBP-1 lactylation in macrophages in acute lung injury

Dan Wang¹Yi Gong²Yehao Chen³Zhefan Wang⁴Jinxiang Yin⁴Zhengrui Wang⁴Xiao Yang⁴Yizhou Zhang⁴Jie Huang⁵Zhengyu Jiang^6*

• ¹Shanghai Changzheng Hospital, Shanghai, China
• ²Huashan Hospital Fudan University, Shanghai, China
• ³Naval Medical University, Shanghai, China
• ⁴Yangpu Senior High School, Shanghai, China
• ⁵Changhai Hospital, Shanghai, China
• ⁶Changhai Hospital, Second Military Medical University, Shanghai, China

Acute lung injury (ALI), characterized by excessive inflammation and cell death, is closely associated with ZBP1-mediated PANoptosis, a programmed cell death mechanism. The intrinsic regulatory mechanism of PANoptosis remains poorly investigated. In this study, we investigated the protective effects of lactate on lipopolysaccharide (LPS)-induced ALI and its potential regulatory role in ZBP1-mediated PANoptosis. Our results showed that lactate effectively reduced inflammatory cytokine (TNF-α, IL-6, and IL-1β) and CD11b+Gr1+ monocyte infiltration in bronchoalveolar lavage fluid and serum. It also alleviated lung pathology and suppressed PANoptosis markers (cleaved caspase-1, GSDMD-p20, phospho-MLKL, and cleaved caspase-3/8). Mechanistically, lactate decreased ZBP1 expression and its interaction with RIPK1 and TRIF while enhancing ZBP1 lactylation. Notably, the ZBP1 agonist CBL0137 reversed the protective effects of lactate. In vitro experiments demonstrated that lactate inhibited LPS+5z7-induced PANoptosis in macrophages by reducing the ZBP1-RIPK1-TRIF interaction and promoting ZBP1 lactylation, which was dependent on MCT1. Thus, our study demonstrated that lactate attenuates ALI by suppressing ZBP1-mediated PANoptosis, possibly through Mct1-related lactylation. The present study revealed the regulatory role of lactate in inflammation and cell death in ALI and suggested a lactylation-associated therapeutic strategy for ALI.