Modulating The PI3K/Akt Pathway To Improve Erectile Dysfunction (ED) With Traditional Chinese Medicine: Monomers, Extracts, Herb Pairs, And Formulas
Dec 29, 2025
Keywords: best herb for erectile dysfunction ED?; PI3K/Akt; eNOS; oxidative stress; Cistanche Tubulosa; echinacoside; isorhamnetin;
proanthocyanidins; piperine; Panax notoginseng saponins; earthworm protein; yam protein; Epimedium; Morinda officinalis; leech-centipede; Curculigo; Albizia flower; Xiaoyao San; testosterone; NRF2
Executive takeaway for R&D/product teams:
The PI3K/Akt/eNOS axis is a central therapeutic pathway for ED across preclinical models, mediating anti-oxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic effects, and endothelial NO production.
Multiple TCM monomers and formulas converge on this pathway, offering multi-target synergy with a favorable safety profile.
Cistanche Tubulosa (C. tubulosa) stands out with robust antioxidant phenylethanoid glycosides (echinacoside, acteoside) that reduce inflammatory markers (TNF-α, IL-6), restore steroidogenic enzymes (StAR, CYP11A1, CYP17A1, HSD17β3), improve testosterone and sperm quality, and support urinary/prostate function-positioning it as a leading candidate for ED support stacks.
For a science-backed ED solution, consider a core stack of standardized Cistanche Tubulosa extract (echinacoside/acteoside) plus targeted adjuncts (icariside II, proanthocyanidins, piperine, Panax notoginseng saponins), all validated in vivo to modulate PI3K/Akt signaling.
TCM Monomers That Regulate the PI3K/Akt Pathway to Improve ED
3.1 Flavonoids
Icariside II (from Epimedium): A flavonoid with broad bioactivities (hormone modulation, antioxidant, anti-inflammatory, vasodilation) [40]. In diabetic ED rats, icariside II combined with metformin significantly increased intracavernosal pressure/mean arterial pressure (ICP/MAP), erection frequency, and erection rate, while reducing oxidative stress markers (ROS). Phosphorylation of PI3K, Akt, p-Akt, mTOR, and p70S6K increased, indicating activation of the PI3K–AKT–mTOR pathway, reduced autophagy, and normalized redox balance to improve erectile function [41]. Additionally, a 4-week course of a icariside II derivative (2.5 mg/(kg·d)) significantly improved erectile function in a rat model of cavernous nerve injury-induced ED. It reduced corpus cavernosum smooth muscle fibrosis and enhanced erectile capacity via the PI3K/AKT/eNOS pathway [42].
Isorhamnetin (from Ginkgo biloba and Hippophae): Exhibits antioxidant, antimicrobial, anti-inflammatory, and cardioprotective effects [43]. In diabetic ED rats, oral isorhamnetin (10/20 mg/kg for 4 weeks) enhanced erectile function and increased smooth muscle content. It reduced IL-6, TNF-α, and malondialdehyde (MDA), while boosting anti-inflammatory cytokines and antioxidant enzymes SOD and catalase. Under high-glucose conditions or PI3K inhibition, p-PI3K, p-AKT, and p-eNOS were reduced; isorhamnetin reversed these changes, implicating PI3K/AKT/eNOS signaling in its pro-erectile mechanism [19].
A HERB SUPPLEMENT SELL IN CHINA FOR PENIS ENLARGEMENT
3.2 Polyphenols
Proanthocyanidins: Widely present in raspberry, hawthorn, and ginkgo; known for antioxidant, anti-inflammatory, and cardioprotective properties [44]. In diabetic ED rats, doses of 50, 100, 150 mg/kg improved ICP/MAP, decreased endothelin-1 and LOX-1, and increased NO. They also improved testosterone synthesis milieu and elevated T levels. Network pharmacology, ELISA, and qPCR indicated increased AKT and decreased Caspase-3, supporting PI3K/Akt modulation, sex hormone regulation, and anti-apoptosis as mechanisms in diabetic ED [45].
TCM HERB CISTANCHE BASED FUMULA WITH HIGH POLYPHENOLS
3.3 Alkaloids
Piperine (from black pepper): With analgesic, anti-inflammatory, antioxidant, and antimicrobial activities [46]. In diabetic ED rats, 20 or 40 mg/kg piperine for 8 weeks improved erectile function, reduced fibrosis, decreased total and mitochondrial ROS, lowered Caspase-3 and BAX, and increased SOD and MMP. Mechanistically, it likely acts via PI3K/AKT/NRF2 to attenuate fibrosis, oxidative stress, and apoptosis, while protecting mitochondrial function [47].
3.4 Phenylpropanoid Glycosides
Echinacoside (from Cistanche): Isolated from the stems of Cistanche; demonstrates antioxidant, anti-aging, anti-inflammatory, hepatoprotective, and neuroprotective effects [48]. Echinacoside induces NO production and eNOS phosphorylation in endothelial cells. In vitro, 0.01–10 μM echinacoside increases eNOS Ser1177 phosphorylation and Akt Ser473 phosphorylation in a concentration-dependent manner, indicating PI3K/Akt-dependent eNOS activation and NO generation; thus, it can enhance endothelial relaxation and erectile function [49].
3.5 Saponins
Panax notoginseng saponins (PNS): A mixture of steroidal and triterpenoid saponins with cardiovascular, immunomodulatory, neuroprotective, and anti-inflammatory effects [50]. At 50/100/150 mg/kg, PNS increased ICP and ICP/MAP in diabetic ED rats; raised SOD, glutathione (GSH), Akt, and Bcl-2; and reduced MDA and Bax-consistent with PI3K/Akt activation as the mechanism for erectile improvement [51].
TCM Extracts and Herb Pairs That Regulate the PI3K/Akt Pathway
4.1 Earthworm Extract (Dilong protein)
Rich in lumbrokinase and trace elements; functions include clearing heat, unblocking channels, antiasthmatic, and diuretic effects [52]. In diabetic ED models, 0.045/0.090/0.180 g/kg Dilong protein for 4 weeks increased ICP/MAP, reduced corpus cavernosum fibrosis and apoptosis, and elevated PI3K, AKT, p-AKT, and Bcl-2 expression-indicating erectile improvement via PI3K/Akt-mediated anti-apoptotic and anti-fibrotic actions [53].
4.2 Yam Extract (Dioscorea)
Contains polysaccharides and saponins; exerts antioxidant and hormone-modulating effects. Yam protein at 0.6, 0.9 mg/(kg·d) significantly improved "kidney yang deficiency"-type ED in rats and normalized corpus cavernosum histology. p-PI3K/PI3K, p-AKT/AKT, and p-eNOS/eNOS increased, indicating activation of PI3K/AKT/eNOS to promote endothelial NO release and penile erection [33].
4.3 Epimedium–Morinda officinalis (Yinyanghuo–Bajitian)
Network pharmacology identified quercetin, kaempferol, stigmasterol, and luteolin as key compounds. PI3K–AKT signaling is central; connexin 43–mediated gap junctions in smooth muscle modulate contraction/relaxation in response to autonomic NO signals. Anti-inflammatory mechanisms also contribute [54].
4.4 Leech–Centipede (Shuizhi–Wugong)
"Activate blood and resolve stasis" duo. At 0.3 g/(kg·d) for 8 weeks, this pair increased smooth muscle density, serum testosterone, and phosphorylation/mRNA of PI3K, AKT, and mTOR while reducing collagen deposition-suggesting improved erection via PI3K/AKT/mTOR, with anti-apoptosis and anti-fibrosis effects [55].
4.5 Curculigo–Epimedium (Xianmao–Yinyanghuo)
Network pharmacology and molecular docking indicate AKT1 as a key target. The PI3K–AKT axis regulates NOS expression/activity to control NO generation and corpus cavernosum function [56].
Summary tables (not shown) consolidate monomers and formulas acting via PI3K/Akt.
Single Herbs and Formulas Regulating PI3K/Akt to Improve ED
TCM HERB CISTANCHE BASED FUMULA WITH HIGH POLYPHENOLS
Albizia flower (Hehuan Hua): Rich in flavonoids, polyphenols, terpenes; offers antioxidant and antidepressant-like effects. In a psychogenic ED rat model induced by isolation plus chronic unpredictable stress, 0.9/1.8/3.6 g/kg Albizia flower increased mount frequency and intromission ratio, with upregulated PI3K/Akt signaling-supporting efficacy via PI3K/Akt activation [57, 58].
Yishen Tongluo Fang: A multi-herb formula (Achyranthes bidentata, Salvia miltiorrhiza, Epimedium, Cuscuta, Astragalus, Rehmannia, Leech) for warming yang, tonifying kidney, and soothing liver. Core targets include AKT1 and IL6; quercetin is a key active based on network topology. KEGG enrichment ties effects to PI3K–AKT, indicating targeted modulation of this pathway in diabetic ED [59].
Xiaoyao San: Classic formula (Angelica, Poria, Paeonia alba, Atractylodes, Bupleurum, fresh ginger, honey-fried licorice, mint), used for liver-qi stagnation with spleen deficiency. In diabetic ED rats, low/high doses (10.7, 17 g·kg–1) improved ICP/MAP, increased albumin and PI3K/Akt, decreased IL-6/TNF-α, and reduced fibrosis. RAGE/PI3K/Akt is a key target pathway, mediating anti-inflammatory and pro-erectile effects [60].
Tianjing Tongluo Fang: Designed for "kidney essence deficiency and blood stasis" (Epimedium, Rehmannia, Salvia, Achyranthes, etc.). Four-week gavage increased mount/intromission, elevated serum testosterone, and upregulated eNOS and Akt mRNA/protein in cavernosum while reducing connective tissue overgrowth-confirming PI3K/Akt modulation and improved contractile function in diabetic ED [61].
Simiao Biejia Decoction: Multi-herb formula (e.g., Carapax Trionycis, Salvia, Angelica, Licorice, Pueraria, Coptis, Astragalus, Lonicera, Lychee seed, Rehmannia, Scrophularia, Lycium, Epimedium). In diabetic ED rats, 2.44/4.88/9.76 g/kg improved erections, reduced fibrosis, lowered eNOS and nNOS overactivation-associated injury, mitigated oxidative stress, and protected smooth muscle/endothelium. Luteolin is a core component that can bind AKT1, indicating PI3K/AKT pathway involvement [62].
Shugan Yiyang Capsules: Based on qi–blood theory; contains Bupleurum, Tribulus, bee nest, Cnidium, earthworm, leech, Aspongopus, purple radix (zirchashao), Polygala, Cistanche, Cuscuta, Schisandra, Morinda, centipede, Acorus, etc. Upregulates p-Akt1/Akt1 ratio in corpus cavernosum, improves erection, libido, and ejaculation-implicating PI3K/Akt activation [63].
Bushen Huoxue Fang: Contains wine-processed Cistanche, deer antler, Carthamus, ginseng, Achyranthes, etc. At 3 and 6 g/kg/d for 8 weeks, it improved ICP and ICP/MAP, reduced smooth muscle apoptosis/fibrosis, and upregulated p-AKT and AKT in cavernosum-mechanistically linked to PI3K/AKT signaling [64].
Summary and Development Implications
ED pathogenesis is multifactorial; PI3K/Akt is a major pathway in prevention and therapy. Modern interventions like testosterone can precisely target PI3K/Akt/eNOS to suppress oxidative stress and enhance NO/cGMP signaling (improving castrated rat erections) [65]. SS-31, a mitochondria-targeted antioxidant, improves ED by activating PI3K/AKT/eNOS and promoting NO-mediated relaxation [90].
However, modern single-target therapies may have higher adverse effects and translational hurdles. TCM's multi-component, multi-target mechanisms plus lower adverse event profile present unique advantages, especially when focusing on PI3K/Akt modulation.
Evidence synthesis shows numerous TCM monomers, extracts, herb pairs, and formulas can:
Inhibit oxidative stress and apoptosis
Prevent or reverse corpus cavernosum smooth muscle fibrosis
Reduce mitochondrial mitophagy
Attenuate inflammation
Enhance endothelial NO-mediated vasorelaxation
Positioning Cistanche Tubulosa as "Best Herb for Erectile Dysfunction (ED)?"
Mechanistic fit: Echinacoside and acteoside from Cistanche are potent antioxidants that lower ROS and inflammatory cytokines (TNF-α, IL-6); they activate PI3K/Akt/eNOS for NO production and endothelial function [49]. The brand article further documents improved prostate health, urinary symptoms, testosterone synthesis via steroidogenic proteins (StAR, CYP11A1, CYP17A1, HSD17β3), and enhanced sperm parameters-key for male vitality and reproductive health.
Clinical relevance: In diabetic rodent models, Cistanche improved sperm count/motility, reduced abnormalities, and restored steroidogenesis even under AGE stress-ECH sometimes outperforming resveratrol for HSD17β3 restoration.
Safety and practicality: Gentle on digestion; suitable for long-term use and easy to formulate as standardized capsules or powders with defined echinacoside/acteoside content.
Development note: For an ED-targeted nutraceutical, Cistanche Tubulosa is a strong lead as the best herb for erectile dysfunction ED? when standardized to echinacoside (e.g., 10–30%) and acteoside, and combined with adjuncts that also act on PI3K/Akt/eNOS.
Actionable product concept (for R&D):
Core: Cistanche Tubulosa extract standardized to echinacoside + acteoside.
Adjuncts (dose ranges per kg in preclinical data; human translation requires PK/PD scaling and safety):
Icariside II (Epimedium) for PI3K–AKT–mTOR and eNOS support [40–42]
Proanthocyanidins for NO upregulation and anti-apoptosis via AKT [45]
Piperine to activate PI3K/AKT/NRF2, reduce fibrosis and oxidative stress [47] and possibly enhance bioavailability of co-actives
Panax notoginseng saponins for antioxidant/anti-apoptotic synergy via Akt/Bcl-2 [51]
Optional extracts: Earthworm protein (anti-fibrotic), Yam protein (endothelial NO), Albizia flower (psychogenic ED), Xiaoyao San or Bushen Huoxue Fang for comprehensive qi–blood and vascular support.
Biomarkers/endpoints for trials: ICP/MAP, IIEF scores, penile Doppler (PSV/EDV), serum NOx, cGMP, oxidative stress panel (MDA, 8‑iso‑PGF2α), inflammatory cytokines (IL‑6, TNF‑α), testosterone and SHBG, penile tissue Akt/eNOS phosphorylation (if animal/human biopsy feasible).
Cistanche resource for further reading and positioning:
Cistanche and prostate–hormone–fertility synergy: https://www.xjcistanche.com/news/say-goodbye-to-prostate-problems-with-cistanch-83534746.html
Supportive Service Of Wecistanche-For more details about cooperation
Email:wallence.suen@wecistanche.com
References
[19] Mao Y et al. Effect of isorhamnetin on diabetic erectile dysfunction; PI3K/AKT/eNOS involvement.
[33] Li YX et al. Yam protein improves ED via PI3K/AKT/eNOS.
[39] Ye K et al. LIPUS-SCs-Exo promotes nerve regeneration via PI3K/Akt/FoxO in ED rats. CNS Neurosci Ther. 2023;29(11):3239–3258.
[40] Zhang J et al. Icariside II increases cGMP by enhancing NOS in diabetic ED rats. Andrologia. 2012;44(S):87–93.
[41] Zhang J et al. Icariside II + metformin improves erectile function and redox/autophagy in T2DM ED rats via PI3K–AKT–mTOR. Transl Androl Urol. 2020;9(2):355–366.
[42] Zhu L et al. Icariside II derivative YS10 improves nerve injury ED via PI3K/AKT/eNOS. Chin J Integr Tradit West Surg. 2024;30(6):777–781.
[43] Gong G et al. Isorhamnetin: A review. Biomed Pharmacother. 2020;128:110301.
[44] Nie Y, Stürzenbaum SR. Proanthocyanidins: mechanisms and implications. Adv Nutr. 2019;10(3):464–478.
[45] Zeng X, Li L, Tong L. Proanthocyanidins treat diabetic ED in rats. Int J Mol Sci. 2024;25(20):11004.
[46] Li S, Lv M, Xu H. Piperine overview. Mini Rev Med Chem. 2023;23(8):917–940.
[47] Guo Z et al. Piperine ameliorates diabetic ED via PI3K/AKT/NRF2. Food Bioscience. 2025;66:106326.
[48] Luo F et al. Echinacoside and acteoside from Cistanche tubulosa: uric acid–lowering effects. Chin Pharmacol Bull. 2025;41(9):1736–1743.
[49] Gu L et al. Echinacoside-induced NO in endothelial cells via androgen receptor and PI3K–Akt. Int J Mol Med. 2020;45(4):1195–1202.
[50] Qu J et al. Panax notoginseng saponins in CNS disorders. Ann Transl Med. 2020;8(22):1525.
[51] Li H. Effects of PNS on diabetic ED in rats. Master's Thesis, Chongqing Med Univ. 2013.
[52] He YR et al. Earthworm components and pharmacology. Guangxi Med. 2025;47(4):619–622.
[53] Liu LM et al. Dilong protein improves diabetic ED via PI3K/Akt. Chin J Andrology. 2023;37(3):25–33.
[54] Zhang GZ et al. Network pharmacology of Epimedium–Morinda in ED. World J Trad Chin Med. 2021;16(15):2275–2281.
[55] Feng JL et al. Leech–centipede improves diabetic ED via PI3K/AKT/mTOR. J Beijing Univ Trad Chin Med. 2021;44(12):1118–1125.
[56] Zhang F et al. Curculigo–Epimedium mechanisms in ED via network pharmacology/docking. Chin J Andrology. 2022;36(2):51–58.
[57] Wang XY et al. Albizia flower pharmacological basis. World J Trad Chin Med. 2024;19(12):1860–1869.
[58] Qiao Y. Albizia flower for psychogenic ED via PI3K–AKT–mTOR. Doctoral Thesis, Nanjing Univ TCM. 2024.
[60] Mao YH et al. Xiaoyao San improves diabetic ED via RAGE/PI3K/Akt. J Chin Exp Formulae. 2024;30(17):122–130.
[61] Zhang XH et al. Tianjing Tongluo Fang improves corpus cavernosum function in diabetic ED rats. Chin J Trad Chin Med. 2021;36(11):6747–6751.
[62] Liu Y et al. Mechanism of Simiao Biejia Decoction in diabetic ED rats. Drug Des Devel Ther. 2025;19:2609–2628.
[63] Wang J et al. Shugan Yiyang Capsule increases VEGF/IGF/Akt1 in arterial ED rats. Natl J Androl. 2012;18(2):184–188.
[64] Yue ZB. PI3K–AKT-based mechanism of Bushen Huoxue in diabetic ED. Master's Thesis, Beijing Univ TCM. 2016.
[65] Li R. Testosterone suppresses oxidative stress and regulates COX‑2/PTGIS/cAMP to improve ED; targets PI3K/Akt/eNOS. Doctoral Thesis, HUST. 2017.
[90] Du ZJ. SS‑31 improves ED via PI3K/AKT/eNOS activation and NO release.
Further reading on Cistanche's male health benefits:
Say Goodbye To Prostate Problems With Cistanche Tubulosa (肉苁蓉): A Natural, Science-Backed Herbal Solution (includes data on inflammation, antioxidant enzymes, testosterone synthesis, sperm quality, and urinary function): https://www.xjcistanche.com/news/say-goodbye-to-prostate-problems-with-cistanch-83534746.html
