Extremophilic prokaryotes survive salt, temperature, and pH extremes by coordinating stress-induced protein networks that preserve macromolecules, sustain energetics, and repair damage. This review integrates recent proteomics with functional genomics to resolve both network state and causality across halophiles, thermophiles, acidophiles, alkaliphiles, psychrophiles, and radiation-resistant prokaryotes. Quantitative proteomics maps condition-specific induction of chaperones, proteases, ion transporters, osmolyte pathways, DNA repair proteins, antioxidants, and envelope remodeling enzymes. Complementary perturbation genetics, functional genomics, and transcriptomics help to identify essential nodes and regulatory circuits underlying stress tolerance. In halophiles, compatible solute synthesis and Na⁺/H⁺ exchange couple to protein quality control and central metabolism, whereas many archaeal halophiles additionally rely on high intracellular salt and distinctive membrane chemistry. Thermophiles rely on heat-shock systems, ATP-dependent proteolysis, membrane adjustments, and redox balancing. Acidophiles maintain near-neutral cytosol via proton export and low-permeability membranes while linking iron handling to oxidative defense. Alkaliphiles use Na⁺-based bioenergetics, multi-subunit antiporters, and cell-wall modifications to retain protons. Psychrophiles emphasize cold-shock RNA chaperones, flexible enzymes, and cryoprotectants, whereas radiophiles combine exceptional DNA repair with strong antioxidant capacity. Across taxa, oxidative stress forms a cross-cutting axis that explains extensive regulon overlap and cross-protection. We synthesize network architecture, highlight conserved modules and lineage-specific solutions, and outline open questions in stress sensing, multi-stress integration, and the functions of uncharacterized proteins. These insights provide a framework for engineering robust biocatalysts and organisms for biotechnology and environmental applications.

Extremophilic bacteria survive salt, temperature, and pH extremes by coordinating stress-induced protein networks that preserve macromolecules, sustain energetics, and repair damage. This review integrates recent proteomics with functional genomics to resolve both network state and causality across halophiles, thermophiles, acidophiles, and alkaliphiles, with targeted contrasts from psychrophiles and radiation-resistant bacteria. Quantitative proteomics maps condition-specific induction of chaperones, proteases, ion transporters, osmolyte pathways, DNA repair proteins, antioxidants, and envelope remodelling enzymes. Complementary perturbation genetics/functional genomics and transcriptomics help identify essential nodes and regulatory circuits underlying stress tolerance. In halophiles, compatible solute synthesis and Na+/H+ exchange couple to protein quality control and central metabolism. Thermophiles rely on heat-shock systems, ATP-dependent proteolysis, membrane adjustments, and redox balancing. Acidophiles maintain near-neutral cytosol via proton export and low-permeability membranes while linking iron handling to oxidative defence. Alkaliphiles use Na+-based bioenergetics, multi-subunit antiporters, and cell wall modifications to retain protons. Psychrophiles emphasize cold-shock RNA chaperones, flexible enzymes, and cryoprotectants, whereas radiophiles combine exceptional DNA repair with strong antioxidant capacity. Across clades, oxidative stress forms a cross-cutting axis that explains extensive regulon overlap and cross-protection. We synthesize network architecture, highlight conserved modules and lineage-specific solutions, and outline open questions in stress sensing, multi-stress integration, and functions of uncharacterized proteins. These insights provide a framework for engineering robust biocatalysts and organisms for biotechnology and environmental applications.