Tissue & cell · 2026
E3 Ligase KPC1 promotes sepsis-induced liver injury via ubiquitination and processing of NF-κB1 p105 in kupffer cells.
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Chai Lin, Liu Xiaoyu, Luo Ming, Li Ling, Guo Shubin
Аннотация
BACKGROUND: Sepsis-associated liver injury (SALI) is characterized by dysregulated inflammation and NF-κB pathway activation, The E3 ubiquitin ligase KPC1 is known to process NF-κB1 p105 into p50, yet its specific role in SALI remains unclear.
METHODS: Using a murine cecal ligation/puncture (CLP) model and LPS-stimulated human Kupffer cells, we knocked down KPC1 with lentiviral shRNA. Liver injury (ALT/AST), inflammatory cytokines (IL-1β/IL-6/IL-18/TNF-α), LDH release, pyroptosis markers (NLRP3, cleaved caspase-1, GSDMD-N), and survival were assessed. KPC1-p105 interactions, p65 nuclear translocation, promoter occupancy, and ubiquitination were analyzed. Dual knockdown of KPC1 and p105 was performed to confirm pathway specificity.
RESULTS: KPC1 was significantly upregulated in both in vivo and cellular SALI models. KPC1 knockdown improved survival, attenuated liver injury, suppressed inflammatory cytokine and LDH release, and reduced pyroptosis. Mechanistically, KPC1 directly interacted with p105, promoted its ubiquitination, and enhanced its processing into the transcriptionally active p50 subunit. The anti‑inflammatory effect of KPC1 silencing was reversed upon concurrent p105 knockdown, confirming the functional dependence on the KPC1-p105 axis.
CONCLUSION: KPC1 exacerbates SALI by driving p105/NF-κB‑dependent inflammation and pyroptosis in Kupffer cells, highlighting its potential as a therapeutic target for SALI.
METHODS: Using a murine cecal ligation/puncture (CLP) model and LPS-stimulated human Kupffer cells, we knocked down KPC1 with lentiviral shRNA. Liver injury (ALT/AST), inflammatory cytokines (IL-1β/IL-6/IL-18/TNF-α), LDH release, pyroptosis markers (NLRP3, cleaved caspase-1, GSDMD-N), and survival were assessed. KPC1-p105 interactions, p65 nuclear translocation, promoter occupancy, and ubiquitination were analyzed. Dual knockdown of KPC1 and p105 was performed to confirm pathway specificity.
RESULTS: KPC1 was significantly upregulated in both in vivo and cellular SALI models. KPC1 knockdown improved survival, attenuated liver injury, suppressed inflammatory cytokine and LDH release, and reduced pyroptosis. Mechanistically, KPC1 directly interacted with p105, promoted its ubiquitination, and enhanced its processing into the transcriptionally active p50 subunit. The anti‑inflammatory effect of KPC1 silencing was reversed upon concurrent p105 knockdown, confirming the functional dependence on the KPC1-p105 axis.
CONCLUSION: KPC1 exacerbates SALI by driving p105/NF-κB‑dependent inflammation and pyroptosis in Kupffer cells, highlighting its potential as a therapeutic target for SALI.