Methamphetamine impairs stress resistance and extracellular matrix integrity via modulating the unfolded protein...

Methamphetamine (METH) contamination of aquatic environments poses a growing threat to animal health, yet the mechanisms by which extracellular matrix (ECM) alterations influence cellular stress defenses remain poorly defined. Using Caenorhabditis elegans, this study demonstrates that 0.5 μM METH exposure compromises ECM integrity and thereby diminishes survival under ultraviolet, osmotic, and heat stress, reducing stress resistance by approximately 17-37 %. Mechanistically, METH-induced proteotoxicity is critically dependent on ECM integrity. Loss of col-109 or col-120 abrogates METH-induced polyglutamine aggregation and largely blocks the activation of both the endoplasmic reticulum (hsp-4) and mitochondrial (hsp-6, hsp-60, atfs-1) unfolded protein responses (UPR). Conversely, modulation of mitochondrial UPR through atfs-1 gain- and loss-of-function alleles bidirectionally regulates ECM gene expression and chondroitinase (chhy-1), revealing reciprocal ECM-UPR crosstalk. At the organismal level, functional UPR pathways preserve cuticle integrity and stress resilience under METH challenge. These results indicate that the ECM-UPR interplay constitutes an evolutionarily conserved stress-sensing axis, whereby ECM perturbation signals through UPR to maintain proteostasis and barrier function. These findings identify ECM and UPR components as promising biomarkers of environmental METH exposure and suggest that targeting this axis could mitigate xenobiotic-induced toxicity.