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CORRESP
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September 26, 2025

VIA EDGAR

U.S. Securities and Exchange Commission

Division of Corporation Finance

Office of Life Sciences

100 F Street, N.E.

Washington, D.C. 20549

    Attn:
    Lauren Hamill

Laura Crotty

    Re:
    Hyperion DeFi, Inc.

Registration Statement on Form S-3

Filed July 18, 2025

File No. 333- 288776

Dear Ms. Hamill and Ms. Crotty,

On behalf of Hyperion DeFi,
Inc. (“Hyperion DeFi” or the “Company”), we are submitting this letter in response to a letter,
dated July 31, 2025, from the staff  of the Securities and Exchange Commission (the “Commission”) with respect
to the Company’s Registration Statement on Form S-3 filed with the Commission on July 18, 2025 (the “Registration Statement”).
The Company is concurrently filing Amendment No. 1 to the Registration Statement (the “Amended Registration Statement”),
which includes changes to reflect responses to the staff’s comments and other updates.

The numbering of the paragraphs
below corresponds to the numbering of the comments in the letter from the staff. For the staff’s convenience, we have incorporated
the text of the staff’s comments into this response letter in italics. Unless otherwise indicated, page references in the responses
correspond to the page numbers in the Amended Registration Statement. Capitalized terms used in this letter but not otherwise defined
herein shall have the meanings set forth in the Amended Registration Statement.

The responses provided herein
are based on information provided to Covington & Burling LLP.

Registration Statement on Form S-3

Prospectus Summary, page 5

    1.
    We note your disclosure on page 6 that on June 20, 2025, you received approximately $50 million in gross proceeds in connection with the closing of a private placement, the proceeds of which you plan to use to build a reserve of a token called HYPE. We also note the disclosure in your Forms 8-K filed on June 24 and June 27, 2025. Please provide a materially complete description of HYPE and your treasury strategy. In this regard:

    ·
    State how much capital you intend to use to purchase HYPE for the treasury. Disclose how much the private placement net proceeds will be. State whether you will use capital to purchase HYPE for your treasury from the warrants you issued pursuant to the securities purchase agreement, to the extent the warrants are exercised. Disclose whether you have any other plans to raise capital for the treasury.

    ·
    Disclose the terms of your “co-branded Hyperliquid validator with Kinetiq” arrangement.

    ·
    Disclose the amount of HYPE locked up and the related unlocking schedule.

    ·
    Further discuss the HYPE ecosystem and describe the lifecycle of a HYPE transaction.

    ·
    Explain the basis for your statement that HYPE is “one of the…highest revenue generating blockchains in the world.”

    ·
    Explain the custody arrangements for the HYPE you hold or will hold. In that regard we note the statement in your press release dated June 17, 2025 regarding “securing the assets through a partnership with Anchorage Digital.”

    ·
    Provide a separate risk factor addressing material risks related to the securities purchase agreement, the proceeds of which will be used to fund your HYPE treasury.

Response to Comment No. 1:

The Company respectfully acknowledges
the staff’s comment and advises the staff that it has revised the disclosure in the Amended Registration Statement in response to
the staff’s comment.

Specifically:

    ·

On page 6 of the Amended Registration Statement, the Company has noted
that the net proceeds from the private placement (the “June 2025 PIPE”) were approximately $45.0 million, all of which
were used to make initial HYPE purchases, and that the Company intends to use a portion of the proceeds from the exercise of the Warrants
(as defined below), if any, to purchase additional HYPE for its treasury. The Company has also updated the disclosure to indicate that
following the completion of the June 2025 PIPE, the Company has purchased an additional $10.5 million of HYPE for a total of $55.5 million
used for HYPE purchases to date; and that going forward, it intends to raise additional proceeds through equity financings to purchase
additional HYPE for its treasury, although it cannot currently estimate how much it will raise or when such purchases will occur.
The Company has also noted that its other plans to raise capital for the treasury include the use of its at-the-market offering sales
agreement with Chardan Capital Markets LLC (“Chardan ”) and other future equity offerings.

    ·
    On page 6 of the Amended Registration Statement, the Company has updated the
    disclosure to describe its co-branded Hyperliquid validator, Kinetiq x Hyperion, with Kinetiq Labs, Inc., a Delaware corporation
    with its principal place of business located in Brandon, Florida, and further support of its validator operations by Pier Two Pty. LTD, a proprietary company limited by shares, with its principal place of business located in South Brisbane, Australia,
and an institutional staking services provider.

    ·
    On page 5 of the Amended Registration Statement, the Company has updated
the disclosure to note that as of June 30, 2025, no HYPE was staked to the Company’s validator. The Company initialized the staking
process on July 1, 2025, and as of September 19, 2025, it had 834,050.16 HYPE staked to the Kinetiq x Hyperion validator. The unstaking
of staked HYPE can be accomplished at any time. However, the transfer of HYPE back from the “staking balance” to the “spot
balance” requires a 7-day unlocking period. The Company has also updated the disclosure to discuss the total amount of the supply
of HYPE that was circulating as of September 19, 2025.

    ·
    On page 5 of the Amended Registration Statement, the Company has updated the disclosure to further discuss the HYPE ecosystem as well as the lifecycle of a HYPE transaction.

    ·
    On page 5 of the Amended Registration Statement, the Company has updated the disclosure to note that it references various blockchain data tracking sources, including Artemis Analytics and DefiLlama, as the basis for its belief that Hyperliquid is one of the highest revenue-generating blockchains in the world. The metrics referenced are fee generation and total value locked (the total notional value of the assets that are deposited or “locked” in the various smart contract protocols of a blockchain
network) in DeFi.

    ·
    On page 6 of the Amended Registration Statement, the Company has updated the disclosure to discuss its arrangement with Anchorage Digital Bank National Association, which provides the infrastructure used by the Company.

    ·
    On page 11 of the Amended Registration Statement, the Company has added a risk factor titled, “If we are unable to raise sufficient additional capital on acceptable terms, we may be unable to expand or maintain our HYPE reserve, which could adversely affect our liquidity, financial condition and growth prospects.” In addition, the Company respectfully directs the staff to the risk factor, titled, “HYPE is a highly volatile asset, and fluctuations in the price of HYPE may influence our financial results and the market price of our listed securities,” on page 10 of the Amended Registration Statement, regarding certain risks of investing in HYPE. The Company also believes that the risk factors included in the Company’s Current Report on Form 8-K filed on June 27, 2025, which are incorporated by reference into the Registration Statement, adequately address the risks of investing in HYPE and the Company’s use of capital to fund our HYPE treasury strategy.

General

    2.
    Given the nature of your resale offering, including the size of the transaction relative to the number of outstanding shares held by non-affiliates, the nature of your relationship with Hyperion DeFi Holdings, LLC, and the amount of time Hyperion DeFi Holdings, LLC has held its securities, it appears that the transaction may be an indirect primary offering on behalf of the registrant. Please provide us with a detailed legal analysis of your basis for determining that it is appropriate to characterize the transaction as a secondary offering under Securities Act Rule 415(a)(1)(i). For guidance, refer to Securities Act Rules Compliance & Disclosure Interpretation 612.09.

Response to Comment No. 2:

The Company acknowledges the
staff’s comment and respectfully submits that the transaction is a secondary offering under Rule 415(a)(1)(i) promulgated under
the Securities Act of 1933, as amended (the “Securities Act”).

Background

The Company entered into a
securities purchase agreement on June 17, 2025 (the “Purchase Agreement”) for the June 2025 PIPE with institutional
accredited investors identified therein (the “Purchasers”), including HLIP Holdings, LLC (“HLIP”),
formerly Hyperion DeFi Holdings, LLC. Pursuant to the Purchase Agreement, the Purchasers purchased an aggregate of 5,128,205 shares of
the Company’s Series A Non-Voting Preferred Stock, par value $0.0001 per share (the “Series A Preferred Stock”)
and warrants (the “Purchaser Warrants”) to purchase 200% of the number of shares of the Company’s common stock,
par value $0.0001 per share (the “Common Stock”) issuable upon full conversion of the Preferred Shares, for an aggregate
purchase price of approximately $50 million. The Company also issued warrants to purchase 1,846,153 shares of Common Stock at an exercise
price of $3.25 per share (the “Placement Agent Warrants”) and 307,962 shares of Series A Preferred Stock (together
with the shares of Series A Preferred Stock issued to the Purchasers, the “Preferred Shares”) to Chardan (the “Placement
Agent”) as compensation for its services as placement agent in connection with the June 2025 PIPE pursuant to the Engagement
Letter, dated June 17, 2025, by and between the Company and Chardan (the “Engagement Letter”).

Pursuant to the Certificate
of Designation of Preferences, Rights and Limitations filed with the Secretary of State of the State of Delaware on June 20, 2025 (the
 “Certificate of Designation”), holders of Series A Preferred Stock are entitled to receive dividends on their shares
equal to an annual rate of 6%, payable quarterly in arrears in cash or, at the Company’s option, shares of Common Stock (the “In-Kind
Dividends”).

Also on June 17, 2025, the
Company also entered into the Fourth Amendment (the “Fourth Amendment”) to the Supplement to that certain Loan and
Security Agreement, dated November 22, 2022 (the “Loan and Security Agreement”) with Avenue Capital Management II,
L.P., as administrative agent and collateral agent, Avenue Venture Opportunities Fund, L.P., as a lender (“Avenue 1”)
and Avenue Venture Opportunities Fund II, L.P., as a lender (“Avenue 2” and, together with Avenue 1, the “Lenders”
and the Lenders, together with the Purchasers and the Placement Agent, the “Selling Shareholders”). In connection with
the Fourth Amendment, the Company issued to the Lenders warrants (the “Lender Warrants” and together with the Purchaser
Warrants and Placement Agent Warrants, the “Warrants”) to purchase an aggregate of 350,000 shares of Common Stock at
an exercise price of $4.00 per share.

On July 18, 2025 the Company
filed the Registration Statement for up to 50,770,667 shares of Common Stock (the “Shares”), which includes:

    i.
    Up to 15,384,615 shares of Common Stock issuable upon conversion of the Preferred Shares issued to the Purchasers pursuant to the Purchase Agreement;

    ii.
    up to 30,769,230 shares of Common Stock issuable upon the exercise of the Purchaser Warrants;

    iii.
    up to 923,076 shares of Common Stock issuable upon the conversion of the Preferred Shares issued to the Placement Agent pursuant to the Engagement Letter;

    iv.
    up to 1,846,153 shares of Common Stock issuable upon the exercise of the Placement Agent Warrants;

    v.
    up to 1,497,593 shares of Common Stock issuable as In-Kind Dividends; and

    vi.
    up to 350,000 shares of Common Stock issuable upon the exercise of the Lender Warrants.

Analysis

In an effort to assist registrants
in determining whether an offering by selling shareholders may be characterized as a secondary offering that is eligible to be made on
a shelf basis under Rule 415(a)(1)(i), the staff issued Interpretation 612.09 in its Securities Act Rules Compliance and Disclosure Interpretations
(“C&DI 612.09”). C&DI 612.09 provides that “[t]he question of whether an offering styled a secondary
one is really on behalf of the issuer is a difficult factual one, not merely a question of who receives the proceeds” and that consideration
be given to the following factors:

    ·
    how long the selling shareholders have held the shares;

    ·
    the circumstances under which the selling shareholders have received the shares;

    ·
    the relationship of the selling shareholders to the issuer;

    ·
    the number of shares being sold;

    ·
    whether the selling shareholders are in the business of underwriting securities; and

    ·
    whether under all the circumstances it appears that the seller is acting as a conduit for the issuer.

Each of the relevant factors
listed in C&DI 612.09 is discussed below. Based on an analysis of the specific factors listed in C&DI 612.09 and all the circumstances
applicable to the Company, the Company respectfully submits that the transactions described herein are appropriately characterized as
transactions that are eligible to be made under Rule 415(a)(1)(i).

A. How Long the Shares Have
been Held

The Preferred Shares and Warrants
were, and the Shares, if and when issued, will be, issued in transactions in reliance on the exemption from registration provided by Section
4(a)(2) of the Securities Act and/or Rule 506 promulgated thereunder, or under any applicable state securities laws. Under the Purchase
Agreement and the Lender Warrants, the Purchasers and Lenders, respectively, represented to the Company that they were accredited investors
within the meaning of Regulation D promulgated under the Securities Act and that they were acquiring the securities for investment only
and not with a view toward, or for resale in connection with, the public sale or distribution thereof. The Placement Agent is an accredited
investor within the meaning of Regulation D promulgated under the Securities Act. The Preferred Shares and Warrants, and the Shares issuable
pursuant to the terms of the Preferred Shares and the Warrants, were offered without any general solicitation by the Company or its representatives.

Generally, the longer shares
are held, the less likely it is that the selling shareholders are acting as a mere conduit for the Company. However, the Company notes
that there is no mandatory holding period for a private investment in public equities (a “PIPE”) transaction, such
as the June 2025 PIPE, or for the other private transactions discussed herein, to be characterized as a private placement. As noted by
the staff in Interpretation 139.11 in the Securities Act Sections Compliance and Disclosure Interpretations (“C&DI 139.11”),
a valid secondary offering could in theory occur immediately following the closing of a private placement. C&DI 139.11 provides as
follows:

“In a PIPE transaction, a company
will be permitted to register the resale of securities prior to their issuance if the company has completed a Section 4(2)-exempt sale
of the securities […] to the investor, and the investor is at market risk at the time of filing of the resale registration statement.
The investor must be irrevocably bound to purchase a set number of securities for a set purchase price that is not based on market price
or a fluctuating ratio, either at the time of effectiveness of the resale registration statement or at any subsequent date. […]
There can be no conditions