Table 1.

Therapeutic strategies targeting diverse pathogenic mechanisms. An asterisk (*) denotes well-established therapies, typically approved by the FDA or recommended by multiple national guidelines or expert consensus.

Target	Management Options	Pharmacological Effects	Current Clinical Trials
Immune Dysregulation	Azelaic acid *	Suppresses expression of KLK5 and cathelicidin, activates PPARγ to exhibit anti-inflammatory properties, and curbs expression of IL-1, IL-6, and TNF-α	FDA-approved
	ε-aminocaproic acid	Inhibits KLK5	Shows beneficial impact on the severity of rosacea in a small, randomized pilot trial [192]
	Doxycycline (sub-antibiotic doses) *	Inhibits chemotaxis and ROS production in neutrophils, suppresses several MMPs and subsequent antimicrobial peptide production, targets abnormal amino acid metabolism and sebaceous gland cells	FDA-approved
	Isotretinoin *	Modulates TLR2 expression negatively in keratinocytes, reduces sebum production and sebaceous gland size	Supported by guidelines or expert consensus [2,5,7,197]
	Pimecrolimus *	Inhibits T cell and mast cell activation by blocking calcineurin action	Supported by guidelines or expert consensus [2]
	Tacrolimus	Inhibits calcineurin	Clinical trials conducted with varying numbers of participants (1 to 200) in a systematic review of 28 articles [201]
	Hydroxychloroquine	Attenuates LL37-induced mast cell activation partly by inhibiting calcium influx	Small-sample, multicenter randomized controlled trial comparing hydroxychloroquine to standard doxycycline treatment showed similar efficacy and safety [202]
	Artemether	Suppresses expression of inflammatory biomarkers induced by LL37 via inhibition of transcription factors NF-κB, mTOR, and STAT	Randomized pilot study including 130 subjects evaluated efficacy of artemether emulsion [206]
	Tranexamic acid	Suppresses expression of KLK5, Camp, and TLR2, suppresses expression of cytokines and chemokines, inhibits angiogenesis induced by LL37, inhibits serine protease and physical interaction between urokinase-type plasminogen activator and the stratum corneum	Small-sample clinical trials and case studies have shown effectiveness of tranexamic acid, administered via different routes [209,210,211,214]
	ACU-D1	Inhibits activation of NF-κB	Shows efficacy in double-blind, randomized, placebo-controlled study involving 40 patients [215]
	Secukinumab	Blocks IL-17	Small open-label study conducted [217]
Vascular Dysregulation	Brimonidine tartrate *	α2-adrenergic receptor agonist, promotes contraction of vascular smooth muscle cells	FDA-approved
	Oxymetazoline *	α1-adrenergic receptor agonist, promotes contraction of vascular smooth muscle cells	FDA-approved
	Timolol	Nonselective β-adrenergic receptor blocker, induces vasoconstriction, inhibits inflammatory mediators such as MMPs and IL-6, inhibits angiogenesis by downregulating VEGF, promotes migration and re-epithelialization of keratinocytes, affects the secretion of lamellar bodies mediating repair of the skin barrier	Pilot trial found long-term topical use improved erythema, but rebound occurred after discontinuation; small trial showed significant improvement in erythema with nightly use for 28 days; larger trial found improvement in clinical parameters, but did not reach statistical significance [223,224]
Neurological and Psychological Factors	Botulinum toxin	Inhibits release of vasodilating acetylcholine, regulates NPs such as SP, CGRP, and VIP, reduces mast cell count and degranulation, decreases expression of certain MMPs, reduces sebum production, and increases skin hydration	Limited clinical trials with small sample sizes, imperfect study designs, and short follow-up times suggest potential efficacy and safety for rosacea treatment [230,231,232,233]
	Paroxetine	Inhibits the reuptake of 5-HT	Demonstrated efficacy in a multicenter randomized controlled trial [236]
	Sumatriptan	5-HT1B/1D receptor agonist, inhibits degranulation of mast cells, reduces PACAP levels	Alleviates features of rosacea in double-blind, randomized, placebo-controlled, cross-over trial and successful treatment of severe and painful flushing in a single case report [237,238]
	Propranolol	β-adrenergic receptor blocker, reduces sympathetic activity and alleviates anxiety symptoms	Beneficial impact in some small-sample studies and case reports [239,240]
	Carvedilol	Has both α1 receptor blocking and non-selective β receptor blocking effects, slows heart rate by acting on cardiac β1-adrenergic receptors to reduce patient tension and anxiety, and exerts anti-inflammatory effects by inhibiting NLRP3 inflammasome and the expression of TLR2 in macrophages	A large-scale randomized controlled trial showed that oral carvedilol exhibited better efficacy than topical brimonidine [244,245]
Microbial Dysbiosis	Metronidazole *	Exerts acaricidal effects via its active metabolites, reduces ROS production and scavenges reactive species, impairs IL-17 induction	FDA-approved
	Ivermectin *	Eliminates Demodex mites, reduces neutrophil response, stimulates production of anti-inflammatory cytokines such as IL-10, inhibits pro-inflammatory cytokines like IL-1b and TNF-α	FDA-approved
	Omiganan	Rapidly kills bacteria and fungi	Phase III clinical trial showed effectiveness and safety in severe papulopustular rosacea [253]
	Rifaximin	Treats SIBO by inhibiting bacterial RNA synthesis	Several clinical trials and case reports have shown that rifaximin effectively improves rosacea characteristics in SIBO patients [113,114,238,254,255,256]
Physical Therapy	IPL, Nd:YAG, PDL, and KTP *	Primarily targets sebaceous glands, hemoglobin, and pigmentation	Supported by guidelines or expert consensus [2,5,7,197,248]
	Ablative laser resurfacing *	Targets water, causes vaporization and ablation effects	Supported by guidelines or expert consensus [2,5,7,197,248]
	Photodynamic therapy	Activates photosensitizers with light to generate ROS, modulates immunity and pilosebaceous units, targets Demodex mites, and exhibits antimicrobial effects	Systematic review of nine Level 4 studies suggests PDT may be a safe and effective treatment option; findings from ongoing and smaller-scale trials indicate that PDT may offer efficacy comparable to that of first-line therapies in addressing PPR; results from larger randomized controlled trials combining PDT with other modalities indicate improved efficacy and milder adverse reactions [263,264,265,268,269,270]
	Pro-yellow laser	Emits laser with a wavelength of 577 nm, demonstrating preferential absorption by hemoglobin	Demonstrated efficacy in select case reports and small sample trials; a retrospective study identified reduction of mite density [272,273,274,275,276]
	Radiofrequency	Generates thermal energy, has positive effects on the nervous system, cardiovascular system, immune system, and reduces burning sensations by decreasing TRPV1 expression	Randomized, controlled, split-face study showed radiofrequency and PDL equally effective in treating ETR; radiofrequency treatment showed greater improvement in PPR [280]
	Short-wave radiofrequency	Enhances local blood oxygen supply, repairs skin barriers, and reduces chronic inflammation	Prospective, single-arm, open-label pilot study reported rapid and sustained improvement in mild to moderate ETR patients [278]
	Fractional microneedling radiofrequency	Delivers thermal energy through targeted microneedles, reduces dermal inflammation, mast cell count, and the expression of TLR2, LL37, VEGF, NF-κB, IL-8, and TRPVs	Prospective, randomized, split-face clinical trial showed modest but statistically significant improvement in rosacea [281]
	Ultrasound	Restores skin barrier function by inhibiting MMPs	Both retrospective and prospective studies have reported significant improvements in patient self-assessment and clinical measures [283,284,285,286]