Post-COVID syndrome is predominantly characterized by persistent fatigue that cannot be attributed to other underlying diseases or relieved by conventional rest. Such symptoms may last for weeks to months, substantially impairing patients' health status and quality of life. Nevertheless, current understanding of the pathogenesis of post-COVID syndrome remains insufficient, posing major challenges to its effective clinical management. Therefore, this review elaborates comprehensively on the pathogenesis, potential therapeutic targets, and pharmacological interventions for post-COVID syndrome, aiming to provide evidence for drug research and development as well as clinical application. Four interrelated pathogenic mechanisms sustaining chronic inflammation after viral clearance are collectively involved in disease progression, including immune dysregulation accompanied by chronic low-grade inflammation, mitochondrial dysfunction and impaired energy metabolism, renin-angiotensin system imbalance, and gut microbiota dysbiosis with disrupted gut-brain axis function. Based on these mechanistic findings, this review highlights potential therapeutic targets such as TLR4/TLR7, the JAK/STAT pathway, the NLRP3 inflammasome, the AMPK/NRF2 axis, and the PINK1/Parkin pathway. Accordingly, we summarize mechanism-targeted candidate drugs, including Toll-like receptor antagonists, JAK inhibitors, probiotics, mitochondria-targeted agents and drugs correcting renin-angiotensin system imbalance. In addition, this review summarizes other therapeutic candidates acting via distinct mechanisms, such as fluvoxamine, coenzyme Q10 combined with alpha-lipoic acid, astragalus root extracts, other medicinal herbs and traditional Chinese compound formulas. Post-COVID syndrome represents a complex public health challenge. Further in-depth mechanistic research and rational application of emerging technologies are still required to develop therapeutic strategies for preventing and alleviating the onset and progression of post-COVID syndrome.
