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Background <p>Lupus nephritis (LN) is driven by podocyte pyroptosis triggered by NLRP3 inflammasome activation, yet the dual regulatory mechanisms—transcriptional control by the AP-1 complex (c-JUN/c-FOS heterodimer) and post-translational modulation via lactate-induced NEDD4 lactoylation mediated by the c-JUN/c-JUN homodimer—remain poorly understood. We hypothesized that AP-1 promotes LN progression by (1) directly activating NLRP3 transcription and (2) indirectly inhibiting NLRP3 ubiquitination through c-JUN-driven glycolytic lactate production.</p> Methods <p>Renal tissues from LN patients and MRL/lpr mice were analyzed for c-JUN/c-FOS expression. Podocytes stimulated with LN serum were used to evaluate (1) transcriptional regulation of NLRP3 and key glycolytic enzymes via AP-1 inhibition and (2) the role of lactate in NEDD4 lactoylation and NLRP3 protein degradation.</p> Results <p>Elevated c-JUN and c-FOS levels were observed in renal tissues of both LN patients and MRL/lpr mice. In vitro, lactate suppressed NEDD4-mediated ubiquitination of the NLRP3 inflammasome through NEDD4 lactoylation, explaining why lactate inhibitors attenuated LN serum-induced podocyte pyroptosis. Knockdown of either c-JUN or c-FOS reduced NLRP3 transcription and podocyte pyroptosis, but only c-JUN upregulated glycolytic enzymes to produce lactate and promote NEDD4 lactoylation, highlighting its unique role.</p> Conclusions <p>AP-1 drives LN pathogenesis through a dual mechanism: the c-JUN/c-FOS heterodimer directly activates NLRP3 transcription, while the c-JUN homodimer indirectly stabilizes NLRP3 by enhancing lactate-dependent NEDD4 lactoylation. These findings reveal subunit-specific roles of AP-1 in transcriptional and post-translational regulation, providing novel therapeutic targets for LN.</p>

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Dual-mechanistic regulation of podocyte pyroptosis in lupus nephritis by the AP-1 complex: transcriptional activation of NLRP3 and lactate-mediated ubiquitination inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月21日

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  • Pei-lei Chen,
  • Quan-min Zhou,
  • Dao-lin Cui,
  • Xiao-ying Li,
  • Xiao-min An,
  • Fang Zhao,
  • Shuang He,
  • Xiao-xue Tian,
  • Ying-qin Luo,
  • Lin-jie Li,
  • Ting-ting Wang,
  • Wei-yu Chen,
  • Ling Chen,
  • Xue-rong Zhou,
  • Xin-yu Cheng,
  • Hui-mei Zou,
  • Bing Guo,
  • Fan Zhang

摘要

Background

Lupus nephritis (LN) is driven by podocyte pyroptosis triggered by NLRP3 inflammasome activation, yet the dual regulatory mechanisms—transcriptional control by the AP-1 complex (c-JUN/c-FOS heterodimer) and post-translational modulation via lactate-induced NEDD4 lactoylation mediated by the c-JUN/c-JUN homodimer—remain poorly understood. We hypothesized that AP-1 promotes LN progression by (1) directly activating NLRP3 transcription and (2) indirectly inhibiting NLRP3 ubiquitination through c-JUN-driven glycolytic lactate production.

Methods

Renal tissues from LN patients and MRL/lpr mice were analyzed for c-JUN/c-FOS expression. Podocytes stimulated with LN serum were used to evaluate (1) transcriptional regulation of NLRP3 and key glycolytic enzymes via AP-1 inhibition and (2) the role of lactate in NEDD4 lactoylation and NLRP3 protein degradation.

Results

Elevated c-JUN and c-FOS levels were observed in renal tissues of both LN patients and MRL/lpr mice. In vitro, lactate suppressed NEDD4-mediated ubiquitination of the NLRP3 inflammasome through NEDD4 lactoylation, explaining why lactate inhibitors attenuated LN serum-induced podocyte pyroptosis. Knockdown of either c-JUN or c-FOS reduced NLRP3 transcription and podocyte pyroptosis, but only c-JUN upregulated glycolytic enzymes to produce lactate and promote NEDD4 lactoylation, highlighting its unique role.

Conclusions

AP-1 drives LN pathogenesis through a dual mechanism: the c-JUN/c-FOS heterodimer directly activates NLRP3 transcription, while the c-JUN homodimer indirectly stabilizes NLRP3 by enhancing lactate-dependent NEDD4 lactoylation. These findings reveal subunit-specific roles of AP-1 in transcriptional and post-translational regulation, providing novel therapeutic targets for LN.