Convergent mitochondrial toxicity of fluorinated agents in oncological anaesthesia: sevoflurane, 5-fluorouracil, and the ACOD1/itaconate immune axis

Abstract

Aconitate decarboxylase 1 (ACOD1, formerly IRG1) and its product itaconate have emerged as central regulators of tumour immune surveillance: ACOD1-derived itaconate in tumour-associated macrophages (TAMs) suppresses inflammatory gene expression and limits CD8⁺ T-cell infiltration, while systemic itaconate modulates NLRP3 inflammasome activity and natural killer (NK) cell function. We propose that two agents routinely co-administered in fluoropyrimidine-treated oncological patients—sevoflurane and 5-fluorouracil (5-FU)—may converge on aconitase 2 inhibition, depleting the cis-aconitate substrate for ACOD1 and thereby disrupting itaconate-dependent immune regulation at a critical perioperative window. The fluoroacetate pathway of 5-FU is experimentally established; sevoflurane undergoes CYP2E1-mediated metabolism to fluorinated intermediates whose further biotransformation may generate aconitase-inhibitory species, as suggested by the work of Karpinski et al. (2006) and supported by prospective metabolomic evidence (Wei et al., 2021) demonstrating plasma metabolomic patterns consistent with aconitase perturbation in sevoflurane-anaesthetised patients. The immunological consequences of perioperative ACOD1/itaconate depletion—paradoxically encompassing both pro-tumorigenic immune evasion at the tumour microenvironment level and heightened systemic inflammatory susceptibility—represent a potentially unrecognised dimension of anaesthetic pharmacology in oncological surgery. Pre-operative dual genotyping for dihydropyrimidine dehydrogenase (DPYD) and ACOD1 variants is proposed as a pharmacogenomic framework for anaesthetic technique selection.