Cardiomyocyte-enriched OTUD5 alleviates septic cardiomyopathy by promoting NLRP3 deubiquitination and inhibiting NLRP3 inflammasome activation.

BACKGROUND

Septic cardiomyopathy (SCM) is the leading cause of mortality among patients diagnosed with sepsis. Nevertheless, the precise mechanisms underlying its pathogenesis remain poorly understood. Deubiquitinating enzymes (DUBs) play a vital role in various cardiovascular diseases.

METHODS

This study investigated deubiquitinating enzymes in septic myocardial injury via public RNA-Seq. Pyroptosis was modelled in primary neonatal rat cardiomyocytes using lipopolysaccharide (LPS) and nigericin, with levels assessed by IL‑1β ELISA, Western blot, PI staining, CCK‑8 and LDH assays. Potential substrates of OTUD5 were screened by Co‑immunoprecipitation. Cardiomyocyte‑specific OTUD5‑knockout mice generated by CRISPR/Cas9 were subjected to LPS‑ or Caecal ligation and puncture (CLP)‑induced sepsis models for cardiac function and pyroptosis evaluation. AAV9‑mediated cardiomyocyte‑specific OTUD5 overexpression in NLRP3‑knockout mice was used to validate OTUD5‑NLRP3 functional interaction.

RESULTS

This study identifies the deubiquitinating enzyme OTUD5 as being significantly upregulated in myocardial tissue subjected to sepsis induced by LPS and CLP. Cardiomyocyte-specific knockout of OTUD5 leads to exacerbated septic myocardial injury and pyroptosis. Mechanistically, OTUD5 directly interacted with NLRP3, with its C224 site facilitating deubiquitination to inhibit NLRP3 activation. Notably, the protective effects associated with OTUD5 overexpression were lost in NLRP3 knockout mice, underscoring its dependence on NLRP3 for function.

CONCLUSIONS

This study has confirmed that OTUD5 inhibits pyroptosis by suppressing the activity of NLRP3, thereby ameliorating septic cardiomyopathy. OTUD5 is worthy of further exploration as a potential therapeutic target for septic cardiomyopathy.

KEY POINTS: The expression levels of the deubiquitinating enzyme OTUD5 are elevated in tissues affected by sepsis-induced cardiomyopathy. Cardiomyocyte-specific OTUD5 is a protective factor against myocardial pyroptosis and cardiac dysfunction induced by LPS and CLP. OTUD5 interacts with NLRP3, and its C224 site promotes deubiquitination while inhibiting the activation of NLRP3.